Cancer and Metastasis Reviews (2022) 41:607–625

https://doi.org/10.1007/s10555-022-10043-5

The obesity‑breast cancer link: a multidisciplinary perspective

Emily N. Devericks1 · Meredith S. Carson1 · Lauren E. McCullough2 · Michael F. Coleman1 · Stephen D. Hursting1,3,4

Received: 11 February 2022 / Accepted: 31 May 2022 / Published online: 25 June 2022
© The Author(s) 2022

Abstract
Obesity, exceptionally prevalent in the USA, promotes the incidence and progression of numerous cancer types including
breast cancer. Complex, interacting metabolic and immune dysregulation marks the development of both breast cancer
and obesity. Obesity promotes chronic low-grade inflammation, particularly in white adipose tissue, which drives immune
dysfunction marked by increased pro-inflammatory cytokine production, alternative macrophage activation, and reduced T
cell function. Breast tissue is predominantly composed of white adipose, and developing breast cancer readily and directly
interacts with cells and signals from adipose remodeled by obesity. This review discusses the biological mechanisms through
which obesity promotes breast cancer, the role of obesity in breast cancer health disparities, and dietary interventions to
mitigate the adverse effects of obesity on breast cancer. We detail the intersection of obesity and breast cancer, with an
emphasis on the shared and unique patterns of immune dysregulation in these disease processes. We have highlighted key
areas of breast cancer biology exacerbated by obesity, including incidence, progression, and therapeutic response. We posit
that interception of obesity-driven breast cancer will require interventions that limit protumor signaling from obese adipose
tissue and that consider genetic, structural, and social determinants of the obesity–breast cancer link. Finally, we detail the
evidence for various dietary interventions to offset obesity effects in clinical and preclinical studies of breast cancer. In light
of the strong associations between obesity and breast cancer and the rising rates of obesity in many parts of the world, the
development of effective, safe, well-tolerated, and equitable interventions to limit the burden of obesity on breast cancer
are urgently needed.

Keywords Obesity · Breast cancer · Diet · Health disparities · Adipose · Immune

1 Epidemiology and classification of breast receptor (ER), progesterone receptor (PR), and human
cancer epidermal growth factor receptor 2 (HER2/neu) [2]. Breast
tumors with detectable ER, PR, or both, with or without
In 2020, breast cancer surpassed lung cancer as the leading HER2 amplification, are defined as luminal-like tumors [3].
cause of global cancer incidence in women [1]. Breast cancer Tumors with HER2 overexpression, but not ER or PR, are
is commonly stratified into molecular subtypes identified defined as HER2 + breast cancer [4]. Triple-negative breast
by immunohistochemistry for the presence of the estrogen cancer (TNBC) is defined by a lack of expression of all three
receptors [5]. About 60–90% of all breast cancers express
the androgen receptor, although its potential as a therapeutic
* Stephen D. Hursting target remains controversial [6–8].
hursting@email.unc.edu Luminal A tumors, defined by high ER and PR expression
1
Department of Nutrition, Gillings School of Global Public
without HER2 amplification, is the most common molecular
Health, University of North Carolina at Chapel Hill, subtype of breast cancer with the best prognosis. Luminal
Chapel Hill, NC, USA B, which expresses lower levels of ER and PR and can
2
Department of Epidemiology, Rollins School of Public have HER2 amplification, often presents at a higher tumor
Health, Emory University, Atlanta, GA, USA grade and has a greater risk of recurrence [9]. Both luminal
3
Nutrition Research Institute, University of North Carolina subtypes are generally responsive to endocrine-based
at Chapel Hill, Kannapolis, NC, USA therapies, making effective treatment options more widely
4
Lineberger Comprehensive Cancer Center, University available. However, intrinsic and/or acquired therapeutic
of North Carolina at Chapel Hill, Chapel Hill, NC, USA

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resistance remains pervasive [10]. HER2 + positive breast associated with worse overall survival in patients with early
cancer, accounting for about 20% of breast cancers, is often HER2 + breast cancer, but evidence on the link between
a more aggressive tumor subtype but generally responsive obesity and advanced HER2 + breast cancer is heterogene-
to HER2-targeted therapies [11]. ous [26–28]. Genetic predictors of obesity, including several
While TNBC accounts for only 15–20% of breast cancers, single nucleotide polymorphisms associated with fasting
this intrinsic subtype is particularly aggressive, more likely glucose and insulin, also correlate with breast cancer risk
to metastasize, and due in part to the lack of targeted thera- independent of family history, age, or menopausal status,
pies, results in worse clinical outcomes including greater pointing to the importance of the relationship between obe-
recurrence and lower rates of overall survival [12]. Breast sity, breast cancer risk, and genetics [29, 30].
cancer, particularly TNBC, is a heterogeneous disease, hence
transcriptomic signatures have been developed to further 2.1 Obesity and metastatic progression of breast
stratify these cancers. Basal-like breast cancer (BLBC) is a cancer
particularly aggressive subtype, defined by gene expression
profiles resembling that of basal and myoepithelial breast Metastasis, the dissemination and growth of primary tumor
cells [13]. While not mutually exclusive, BLBC and TNBC cells in secondary sites, is the cause of 90% of tumor-related
are frequently coincident, with TNBC making up 50–75% deaths in patients with breast cancer, with 5-year survival
of BLBC tumors, and about 80% of BLBC tumors lack- rates at 28% for affected patients [31, 32]. Typically, meta-
ing ER and HER2 expression [14]. Additionally, a subset static progression begins with local invasion of cancer cells
of TNBC tumors are defined as claudin-low, characterized from the primary tumor, first into the stroma surrounding the
by a stem cell-like/undifferentiated phenotype, high expres- tumor and eventually to the neighboring normal tissue. Intra-
sion of epithelial-to-mesenchymal (EMT) markers, low vasation follows, as tumor cells expand their niche by enter-
levels of genomic instability, and heightened infiltration of ing lymphatic vessels to access the body’s systemic circula-
stromal and immune cells [15]. When categorized according tion [33]. As a distant site is reached, the cancer cells exit
to intrinsic subtype, 70% of claudin-low tumors are TNBC the bloodstream and proceed to adhere to the target organ.
[16]. TNBC is also characterized by deficiencies in homolo- Metastatic outgrowth marks the final stage of metastatic
gous recombination with the majority of BRCA1 mutation- progression, where quiescent tumor cells at distant sites are
associated breast cancers classified as TNBC [17, 18]. activated to begin proliferating [34, 35]. The mechanisms
behind this activation are part of ongoing research.
For all subtypes of breast cancer, patients who are obese
2 The obesity‑breast cancer link: tend to have larger primary tumors at diagnosis and height-
epidemiological evidence ened risk of developing lymph node metastases [36]. Higher
BMI predicts lower locoregional and distant recurrence-
In 2017–2018, the age-adjusted prevalence of obesity— free survival among women with breast cancer [37], and
defined as a body mass index (BMI) of 30 kg/m2 or greater— increases association with overall mortality when compared
among US adults was 42.4% [19]. Obesity promotes inci- to breast cancer patients at an ideal weight [38]. Indeed,
dence and progression of at least 15 cancer types, including patients with breast cancer and obesity are up to 46% more
breast cancer in postmenopausal women [20]. Adipose tis- likely to have distant metastases 10 years after diagnosis
sue becomes the predominant site of estrogen production [39]. Metabolic syndrome, defined in part by abdominal
after menopause. Hence, women with obesity have greater obesity, in patients with early breast cancer is linked to an
postmenopausal levels of estrogen and consequently greater increased risk of relapse as well as poor prognosis [40].
exposure to estrogen’s protumorigenic effects [21]. Thus, There are both biological and non-biological mechanisms
obesity-mediated exacerbation of cancer is of pressing con- contributing to the disparate outcomes for women with obe-
cern. Across all breast cancer subtypes, obesity is associated sity and breast cancer, which have been expertly reviewed
with worse disease-free survival and overall survival [22]. elsewhere [41].
However, the relationship between obesity and breast can- Obesity expedites and exacerbates metastatic progression
cer is complicated by subtype and menopausal status across of breast cancer, supported by preclinical models [42–44]
the literature. Obesity in women who are postmenopausal and clinical studies [39, 45]. Several leptin-mediated mech-
increases overall relative risk of developing breast cancer anisms behind this link have been established, including
to 1.33, largely driven by increased rates of ER + breast breast cancer invasion, migration, and immune regulation
cancers [23]. However, being obese is also associated with [46, 47], as well as cancer stem cell enrichment and mesen-
postmenopausal TNBC incidence and progression [24, 25]. chymal stem cell dysregulation in the tumor microenviron-
The relationship between obesity and HER2 + breast can- ment [31, 48]. Preclinical models of obesity demonstrate
cer is still incompletely understood. Obesity is consistently that increased myeloid-derived suppressor cell (MDSC)

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recruitment, collagen deposition, and changes in fibroblast to chronic nutrient excess, shifting the body’s energy balance
phenotype in the lungs cooperate to create a favorable prem- signaling network and leading to elevated systemic insulin,
etastatic niche for breast cancer [49]. estrogen, and adipokine signaling [53]. During adipose tis-
sue expansion in the development of obesity, inflammation
arises due to increases in immune infiltration, hypertrophic
3 The obesity‑breast cancer link: molecular adipose tissue remodeling and angiogenesis, adipocyte
mechanisms necrosis, and dysregulated fatty acid flux due to heightened
adipocyte lipolysis [54, 55]. Rapid adipocyte hypertrophy
3.1 Obesity, adipose, and cancer interactions during adipose tissue expansion can create insufficient angi-
ogenesis to achieve proper tissue vascularization, leading
Separately, obesity and cancer are complex, integrating an to hypoxic regions in WAT [56]. WAT hypoxia activates
incompletely understood combination of genetics, environ- the transcription factor hypoxia-inducible transcription
ment, and lifestyle. Hence, the relationship between obesity factor 1, which prevents preadipocyte differentiation and
and cancer is immensely complicated. Despite the complex- initiates adipose tissue fibrosis [57]. Adipose tissue mac-
ity, several mechanisms underlying the obesity-cancer link rophages engulf necrotic or damaged adipocytes to form
have been established. Increased white adipose tissue (WAT) distinct crown-like structures (CLS), a key feature of the
mass is emerging as a nexus of tumor biology and meta- pro-inflammatory process in adipose tissue [58]. Stressed
bolic and inflammatory dysregulation in obesity. WAT is adipose tissue, combined with hypoxia, promotes immune
composed of mature adipocytes, preadipocytes, endothelial cell infiltration and stimulates inflammatory cytokine and
cells, fibroblasts, pericytes, and immune cells [50]. Obe- chemokine release from resident macrophages in adipose
sity also promotes hyperleptinemia, a result of dysregulated tissue [59, 60] (Fig. 1). In addition to inflammatory sign-
adipose tissue that can enhance inflammatory cytokine aling, adipocytes and their precursor mesenchymal stem
secretion [51]. In a murine model of renal cell carcinoma, cells (MSCs) support breast cancer progression by seed-
hyperleptinemia has also been implicated in reduced efficacy ing the tumor microenvironment (TME) with critical sup-
of recombinant adenoviral/TLR agonist and anti-CTLA-4 portive cell populations [61]. Adipose progenitor cells are
checkpoint inhibitor immunotherapy [52]. WAT expands more abundant in obese, relative to nonobese, mice [62],
through adipocyte hypertrophy and hyperplasia in response with greater levels recruited to the TME [63] supporting

Fig. 1  The impact of obesity

on the tumor microenviron-
ment. White adipose tissue from
an obese host is composed of
hypertrophied adipocytes, some
of which become necrotic and
induce formation of crown-
like structures. Adipose tissue
inflammation is furthered by
M1-like and metabolically
activated macrophages. Tumors
developing adjacent to obese
adipose tissue receive numerous
inflammatory and metabolic
signals from adipose and are
marked by immunosuppressed
tumor microenvironment with
ineffective tumor-infiltrating
lymphocytes and immunosup-
pressive M2-like macrophage
polarization. Adipose tissue
further contributes to the tumor
microenvironment via recruit-
ment and transdifferentiation
of cancer-associated fibroblasts
from mesenchymal stem cells,
and adipocyte-derived fibro-
blasts from adipocytes

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breast cancer growth and angiogenesis in vivo [64]. Cancer WAT is a major endocrine organ, secreting hormones and
cells actively reprogram tumor-adjacent adipocyte matrix growth factors, in addition to enzymes and metabolites. The
proteins and the inflammatory secretome, promoting the WAT secretome is an important mediator of tumor exacerba-
formation of cancer-associated adipocytes [65]. Cancer- tion by obesity [81]. Adipokines, secreted by WAT, consti-
associated adipocytes release free fatty acids into the TME tute a class of biologically active polypeptides with a broad
[66], increase interstitial stiffness in breast adipose tissue range of endocrine, metabolic, and inflammatory functions
[67], and enhance secretion of cytokines such as interleukin [89]. Given the extensive interaction between adipocytes and
(IL)-6, interleukin (IL)-8, monocyte chemoattractant pro- tumor cells in the breast TME, adipokines play a critical role
tein (MCP)-1, and tumor necrosis factor-alpha (TNFα), that in the proliferative and invasive capacities of breast cancer
promote inflammation [68]. In addition to supporting tumor [90]. While there are several adipokines (reviewed in [91]),
cell migration, invasion [69, 70], and resistance to therapy two prominent examples are examined below.
[71, 72], cancer-associated adipocytes can transdifferentiate Leptin, the polypeptide hormone primarily produced by
into adipocyte-derived fibroblasts in response to cues from adipocytes, is both synthesized and systemically circulates
the tumor. Adipocyte-derived fibroblasts, along with matrix in proportion to adipose tissue mass [92]. Leptin levels are
metalloproteinases, modify extracellular matrix proteins to higher in patients with breast cancer compared to patients
promote inflammation and tumor invasion [73–76]. Cancer- who are healthy, particularly in women who are overweight
associated fibroblasts, which can arise from a variety of cell or obese [93]. Further, increased leptin associates with breast
types including adipose-derived fibroblasts, are also key cancer risk at a standardized mean difference of 0.96 in a
regulators of tumor development, metastatic progression, meta-analysis of 46 studies of over 13,500 women [94]. Lep-
and therapy resistance [77]. tin impacts breast cancer biology through a myriad of mech-
In addition to modulation of adipocytes and other cells anisms that result in increased tumor volume and metastasis
typically resident in adipose tissue, adipose-adjacent tumors in preclinical and clinical models of breast cancer, including
actively recruit stromal cells, including MSCs, from else- TNBC [33, 95]. Through activation of the PI3K/Akt path-
where in the body, and reprogram their function through way, leptin disrupts breast tissue epithelial polarity and pro-
bidirectional communication with tumor cells to support motes premalignant lesions [96]. High production of reactive
metastatic progression [78]. Cancer cells induce lipolysis oxygen species in TNBC is associated with lower antioxi-
in adipocytes, releasing free fatty acids that are utilized by dant status to favor growth, survival, and inflammation in
tumors for proliferation and migration [79] and stored within the presence of leptin [97]. In a patient-derived xenograft
lipid droplets [66]. This transfer of fatty acids, stimulated model of TNBC, leptin produced by obesity-altered adipose
by cytokines, sustains WAT inflammation [80] and occurs stem cells drove a prometastatic phenotype via upregulation
at a greater rate in breast cancer cells co-cultured with adi- of EMT-associated genes [31]. Increased leptin signaling in
pocytes from donors with obesity versus adipocytes from diet-induced obese mice results in tumoral cancer stem cell
nonobese donors [79]. As breast tissue is composed of enrichment and mediates cell viability, migration, and inva-
90% WAT [81], and the human mammary epithelium is in sion in triple-negative mammary tumor cells [48].
permanent interaction with mammary adipose tissue [82], TNFα is a cytokine expressed in subcutaneous (and to
understanding the impact of excess WAT is imperative to a lower extent, visceral) adipose tissue [98] and preadipo-
resolving the relationship between obesity and breast cancer. cytes [99]. In healthy breast tissue, TNFα contributes to
cell proliferation and morphogenic branching [100]. As a
3.2 WAT and adipokines key pro-inflammatory cytokine, TNFα is also expressed in
monocytes and macrophages, and TNFα levels in adipose
Elevated levels of endogenous sex hormones are associated tissue rise 2.5-fold in individuals with obesity and have a
with obesity and are correlated with a risk of breast cancer strong positive correlation with hyperinsulinemia (r = 0.82)
in postmenopausal women [83]. After menopause, estro- [101, 102]. TNFα promotes leptin secretion from adipocytes
gen production via activity of the key enzyme aromatase [103] and contributes to decreases in the anti-inflammatory
becomes noncyclical and occurs mainly in adipose tissue, adipokine adiponectin [104]. By inducing expression of
exacerbating estrogen production in women with obesity aromatase and IL-6 in adipose tissue, TNFα also promotes
[84]. Obesity not only elevates estrogen production in post- estrogen synthesis [105]. TNFα promotes TNBC migration
menopausal women, but also increases its bioavailability [106] and induces EMT in breast cancer stem cells while
through reductions in sex-hormone binding globulin [85, promoting a claudin-low phenotype [107] implicating this
86]. Increased levels of pro-inflammatory cytokines, such adipokine’s role in metastatic progression. Additionally,
as tumor necrosis factor-α (TNFα) and interleukin (IL)-6, TNFα is linked to TNBC resistance to chemotherapy [108]
further promote estrogen synthesis by inducing aromatase and BLBC resistance to immune checkpoint inhibitors
expression [87, 88]. in vitro [109].

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Thus, obesity dysregulates both endocrine and metabolic higher pro-inflammatory CD4 + ­Th1 cells relative to static
functions of WAT by promoting pro-inflammatory trans- levels of anti-inflammatory ­Th2 cells and regulatory T cells
formation, which is characterized by stromal remodeling, ­(Tregs) in adipose tissue [125]. However, due to aberrant
hypoxia, and altered immune profile. While significant insulin signaling, T­ regs associated with obesity exacerbate
progress has been made in understanding the relationships adipose inflammation through alterations in cytokine pro-
between these complex and intertwined processes, the rela- duction [126].
tive contributions of each of these to the pathophysiology of Obesity-related M1-like macrophages upregulate
obesity remains to be determined. expression of programmed death-ligand 1 (PD-L1; an
immune checkpoint protein) in TNBC, partially through
3.3 Obesity and immune function enhanced secretion of IL-6 [127]. Classified by expression
of the classical dendritic marker CD11c, these M1-polarized
Protumor dysregulation of the prevalence and proportion macrophages contribute to an immunosuppressive micro-
of various immune cells in the obese TME and surrounding environment by promoting T cell exhaustion [128]. While
adipose tissue promotes angiogenesis, tumor growth, meta- the breast TME comprises several types of immune cells,
static spread, and immune evasion culminating in adverse macrophages are the most abundant. Tumor-associated mac-
outcomes for patients with obesity and breast cancer [51, rophages make up over 50% of TME macrophages [129] and
110]. are associated with aggressive features of TNBC tumors,
Adipose tissue remodeling that occurs with weight gain including recurrence and metastases [130]. Leptin also acti-
promotes recruitment of adipose tissue macrophages in vates IL-8 production in tumor-associated macrophages,
both subcutaneous and visceral depots [111, 112]. Classi- driving tumor progression [131]. Metabolically activated
cally activated (M1-like) macrophages are more abundant macrophages are a pro-inflammatory population of mac-
in obese adipose tissue and form the characteristic CLS, rophages unique to obesity and distinct from M1-like mac-
named after their formation of a ring-like network of mac- rophages [132, 133]. Mammary adipose tissue macrophages
rophages surrounding necrotic, hypertrophied, and dying from preclinical models of obesity produce inflammatory
adipocytes in breast adipose, and other WAT [58, 92, 112]. cytokines, induce a stem-like phenotype in breast cancer
These macrophages disrupt adipocyte signaling, increase cells, and promote TNBC growth [132].
reactive oxygen species production, and promote secretion In adipose tissue, lower ­Treg abundance, coupled with
of pro-inflammatory cytokines [58, 113]. The infiltration of an increase in CD8 + T cells, creates an obesity-specific
macrophages and the accompanying inflammation of breast immune profile that promotes macrophage recruitment,
adipose tissue of patients who are obese increases the risk inflammatory cytokine production, and consequently, can
of mammary carcinogenesis [114, 115]. contribute to tumor progression [134, 135]. The increased
In women who are obese, the breast adipose tissue pro- leptin signaling characteristic of obesity increases PD-1
duces CCL2 (also named MCP-1) and IL-1β to recruit mac- expression in T cells, resulting in T cell exhaustion and
rophages and secrete CXCL12, resulting in increased CLS contributing to heightened inflammation [136, 137]. This
formation [116, 117]. The presence of CLS and inflamma- immune dysfunction, however, correlates with greater
tory mediators in breast adipose tissue of women who are response to PD-1/PD-L1 treatment in patients who are
obese is associated with aberrant intracellular signaling and obese, including improvements in CD8 + /CD4 + ratios,
cellular dysfunction [84]. High densities of CLS are also metastatic burden and overall survival [136, 138–141]. This
independently associated with an increased risk of breast relationship is not universal, as reduced anti-PD-1 therapy
cancer, in addition to their negative impact on recurrence efficacy occurs in patients with renal cell carcinoma who are
and survival [118–120]. obese [142]. The impact of obesity on checkpoint blockade
Obesity-related drivers of immunological aging are char- inhibitor response remains unclear in TNBC.
acterized in part by premature thymic involution [121]. Lipid Leptin receptors are highly expressed in activated T cells,
accumulation occurring with obesity can transform thymic impacting their sensitivity to nutrient availability [143]. Lep-
fibroblasts into adipocytes, leading to reduced activity of tin plays an important role in the increased T cell dysfunc-
the thymus [122]. This creates a reduction in the abundance, tion and PD-1 expression seen with obesity [136]. Indeed,
proliferation, and diversity of T cells, the essential players leptin-STAT3 signaling in CD8 + effector T cell metabolism
of cell-mediated immune response and adaptive defense promotes fatty acid ß-oxidation while inhibiting glycolysis
against diseases like cancer [122, 123]. Gamma delta (γδ) in a model of TNBC in high fat diet (HFD)-fed mice [144].
T cells, defined by their γ and δ T cell receptors instead of TNBC tumors from patients who are obese have higher
the canonical α and β T cell receptors, have an increased expression of leptin, CXCR4, and CCR9 (receptors of
pro-inflammatory population in adipose tissue from obese CXCL12 and CCL25, respectively), which negatively cor-
versus nonobese mice [124]. Obesity is also associated with relate with CD8 + T cell infiltration, as compared to tumors

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from patients who are not obese [44]. FasL + granulocytic altered function in a host of immune cells characterized by
MDSC are increased with obesity via leptin signaling, caus- chronic systemic inflammation and limited antitumor immu-
ing CD8 + T cell apoptosis and resistance to immunotherapy nity. Thus, ongoing work to delineate how obesity mediates
[145]. disruption of antitumor immunity, and to identify interven-
Natural killer (NK) cells, type 1 innate lymphoid cells tions to mitigate this is of considerable importance.
that have a large role in tumor response, fall into two dis-
tinct categorizations of CD56 expression. ­CD56dim NK cells
represent an activated phenotype and produce perforin and 4 The obesity‑breast cancer link: health
granzyme for cytotoxic functionality, while ­CD56bright NK disparities
cells serve a more regulatory role [146]. NK cell populations
are reduced both in number and activity in obesity, with 4.1 Obesity biases in breast cancer care
a coincident decrease in the cytotoxic C ­ D56dim population
bright
and increase in the regulatory C ­ D56 population [147, Due to the absence of targeted therapies, chemotherapy
148]. Like T lymphocytes, NK cells also express the leptin remains the standard of care for TNBC. As many as 40%
receptor [149]. Chronic exposure to the elevated leptin lev- of patients who are obese receive substantially lower
els associated with obesity alter post-receptor signaling in doses relative to patients who are not obese due to dose
these cells, lowering JAK2 phosphorylation and decreasing calculation that does not incorporate body weight [166,
production of interferon-γ [149, 150]. 167]. Compared to patients who are not obese, patients
MDSCs are an emerging mechanistic link between obe- with breast cancer who are also obese are more likely to
sity and cancer [151]. Inflammatory signaling pathways have their doses capped at an arbitrary body surface area,
promote the activation and downstream immunosuppressive even in the absence of toxicity expected at full intended
function of MDSCs, driving their accumulation and activity doses [168, 169]. This phenomenon was shown to mediate
in tumors as well as adipose tissue [151, 152]. Character- the relationship between obesity and lower breast cancer-
ized by their expression of the cell surface markers Gr1 and specific survival in a large observational cohort study
Cd11b, MDSC populations accumulate threefold in adipose [170]. However, even when dosing accounts for body
tissue of HFD-fed mice compared to their lean counterparts weight, systemic chemotherapy is less effective in patients
after 12 weeks on diet [153]. Increased levels of circulating who are obese with breast cancer [41]. Tumor-associated
leptin and exogenous lipids both drive immunosuppressive adipocytes can induce multidrug resistance in breast cancer
MDSC accumulation in adipose tissue and the TME, all of by upregulating a transport-associated protein that mediates
which work together to promote tumor growth [154–156]. doxorubicin efflux, a mechanism amplified by obesity [171].
Obesity, in part through crosstalk with leptin and availability In a murine model of TNBC, doxorubicin treatment is less
of lipids in the TME, increases the presence of MDSCs and effective in HFD-fed mice compared to control-fed mice
their PD-L1 expression to enhance tumor progression [154]. due to changes in free fatty acid availability in mammary
Advances in our understanding of the dynamic and com- adipose tissue [172, 173].
plex relationships of the TME, including immune cells, has Despite the improvements in our understanding of the
led to novel therapeutic strategies [157]. The chronically complexity of factors contributing to obesity, coupled with
activated immune response characteristic of obesity can det- its increasingly high prevalence, individuals with obesity
rimentally impact therapeutic efficacy [136, 142]. However, continue to experience stigma and biased treatment in the
as TNBC, relative to other breast cancer subtypes, gener- healthcare setting [174, 175]. This is compounded by the
ally has higher levels of tumor-infiltrating lymphocytes [158] lack of clinical intervention data in patients with cancer and
and increased expression of immune checkpoint molecules, obesity, with obesity status reported in only 5.3% of clinical
immunotherapy has become a promising avenue for PD-1/ trials of obesity-related cancers, including postmenopausal
PD-L1 blockade treatments [159, 160]. An active area of breast cancer [176].
research involves combining immunotherapies with other
treatment modalities, including radiation, targeted therapies 4.2 Obesity and breast cancer health disparities
such as CDK4/6 inhibitors and PARP inhibitors, and can-
cer vaccines, to further improve their efficacy [161–164]. Despite a relatively similar incidence of breast cancer
Another intriguing line of work in the immunotherapy field among non-Hispanic White (NHW) and non-Hispanic
involves the interactions between obesity, immunotherapy Black (NHB) women, NHB women are ~ 40% more likely
response and several cancers [165]. to die of breast cancer [177, 178] and have an overall
Chronic inflammatory signaling in obesity limits immune 5-year breast cancer survival rate of 78.9% (compared
responses to numerous diseases, including cancer. Rather to 88.6% among NHW women) [179]. While there have
than a uniform depression of function, obesity promotes been substantial advances in breast cancer screening

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and treatment, resulting in an overall reduction in breast One potential mechanism of poor outcomes among
cancer mortality, declines are largely attributed to NHB women with luminal A subtypes is obesity-related
improvements among NHW women; the 2018-to-2019 differences in DNA methylation that are associated with
change in the age-adjusted death rate was 19.2 vs. 18.8 several clinical and histopathological features of breast
per 100,000 among NHW women but unchanged among cancer and clinical outcomes [188]. In a study that examined
NHB women [180]. the association between obesity and DNA methylation in
The etiology of racial disparities in breast cancer mortal- NHB and NHW women diagnosed with breast cancer,
ity are multifactorial and include contributing factors from the authors detected interactions with ER status (PSMB1,
social determinants of health and access to tumor biology QSOX1, and PHF1) and race (TOMM20) among the top
and comorbidities. Obesity is an important consideration 20 obesity-associated CpG cites. Additionally, differential
given the known association with risk, recurrence, and mor- methylation at the CpG sites of TOMM20, PSMB1,
tality across age categories and tumor characteristics [181]. and QSOX1 was associated with all-cause mortality,
Profound obesity-related disparities exist in the USA, where suggesting that obesity-related dysregulation may, in
the prevalence rates of both obesity (49.6%) and severe obe- part, drive mortality differences [189]. Other obesity-
sity (BMI ≥ 40 kg/m2) (3.8%) among adults are most pro- related mechanisms may be relevant to differential tumor
nounced among NHB adults compared with other race and progression leading to racial disparities in outcomes,
ethnic groups [19]. Notably, the obesity disparity is largely including local adipose tissue inflammation [190], diversity
driven by NHB women; the 2017–2018 National Health and of the gut microbiome [191], and immune parameters, each
Nutrition Examination Survey showed that the prevalence of which can affect therapeutic effectiveness [192].
of obesity among NHB women was 56.9% compared to While there are several biological links between obesity
39.8% among NHW women [19]. Given the role of obesity and racial differences in breast cancer outcomes, biology
in most aspects of cancer diagnosis, treatment, and progres- alone cannot explain the persistent disparities across age and
sion [182], we posit that obesity could be a causal contribu- subtypes of breast cancer. Evidence suggests that obesity-
tor to racial disparities in breast cancer outcomes, as further related screening biases lead to delayed diagnoses, ultimately
described below. increasing cancer mortality in patients who are obese [182].
One factor in racial disparities in breast cancer Acute and late treatment complications are more often seen
mortality is differences in the presentation and prevalence among women who are obese, and—largely due to dosing
of aggressive tumor subtypes. Specifically, adiposity uncertainty—there remains concern of treatment efficacy
increases the risk of postmenopausal ER + breast in women who are obese [193]. Notably, Black women,
cancer and premenopausal ER-/TNBC [183]. It is well- compared to their White counterparts, are more likely to be
established that NHB women compared to NHW women diagnosed at a later stage and less likely to receive stage-
have a higher incidence of ER-/TNBC [184]. The Carolina appropriate treatment [177]. The confluence of race and
Breast Cancer Study showed that BLBC occurs at a higher obesity-related biases may profoundly affect prognostic
prevalence in premenopausal African American (AA) disparities. In addition to potential obesity-related race
women (39%) compared to postmenopausal AA women differences at the point of care, the inclusion of systemic
(14%) and non-AA women (16%) [185]. BLBC, which inequities is essential to understand obesity-related drivers
progresses more quickly and has greater TP53 mutations of breast cancer disparities. Collin and colleagues recently
compared to the luminal A subtype, are more prevalent in reported a 1.6-fold increase in breast cancer mortality
NHB women and have an unfavorable prognosis. Indeed, among women residing in a redlined Atlanta neighborhood
AA women are more likely to carry a TP53 mutation defined using present-day Housing Mortgage Disclosure
compared to White women [186]. Act data as odds of denial of a mortgage application for
While there is a higher prevalence of premenopausal a residence inside the census tract compared with those
TNBC in NHB compared to NHW women, luminal subtypes outside of the census tract. While only 20% of NHW
remain the most prevalent tumors among NHB women, women diagnosed with breast cancer between 2010 and
accounting for approximately 75% of all breast cancer diag- 2014 lived in a redlined census tract, 80% of NHB women
noses [178]. After adjusting for age, NHB women with lumi- diagnosed during the same time frame lived in redlined
nal A breast cancer have a 2.43 times higher rate of breast areas [194]. Redlining is an important driver of the built
cancer mortality than their NHW counterparts [187]. Given (e.g., food deserts, green space, walkability) and lived (e.g.,
that luminal A breast cancer — compared to TNBC — has environmental toxicants) environments, which profoundly
better treatment options, insights are needed to understand affect adiposity. Additional research is desperately needed to
drivers of such robust disparities in this relatively easier-to- explore the role of structural mechanisms in obesity-related
treat subtype. breast cancer disparities.

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5 Dietary interventions to intercept radiation response by downregulating insulin-like growth

obesity‑mediated exacerbation of breast factor (IGF)-1 receptor signaling, reducing metastatic
cancer tumor burden and improving overall survival in preclinical
models of TNBC [207, 231]. These results were replicated
Obesity can lead to reduced efficacy of existing breast with preclinical models of estrogen-responsive breast can-
cancer therapeutics and increase treatment resistance cer, utilizing the fasting-mimicking diet (described below)
[30, 195]. Patients with obesity experience greater risk and endocrine-based therapies [232]. Some of the meta-
of recurrence following several different endocrine thera- bolic protective effects of CR are mediated through peri-
pies [196–199], and a patient’s BMI at diagnosis correlates ods of fasting, which arise when animals rapidly consume
with breast cancer recurrence across multiple subtypes their daily calories and then fast for the remainder of each
[200]. Side effects during and after treatment, including day [221]. However, this effect has not been examined in
lymphedema, also disproportionately impact women with cancer models. Although CR is not nearly as well char-
obesity [201]. Patients with obesity also face greater risk acterized in clinical studies as it is in preclinical models
of complications resulting from mastectomies, both with [233], human trials show promise in replicating the molec-
and without breast reconstruction surgery [202]. Cancer ular and metabolic changes established in rodents [234].
cell sensitivity to nutrient restriction, as well as their dif- Limited adherence to CR and unsafe weight loss, how-
fering requirements for specific metabolites, constitute ever, particularly in patients with advanced stage cancer,
emergent hallmarks of cancer-targeted therapies [203]. are of major concern for the success of this intervention
Dietary interventions pose an inexpensive and effective [235, 236]. Larger clinical trials that incorporate dietary
way to manipulate availability of key nutrients for tumors components, patient follow-up, and standardized treatment
and hence improve the effect of existing therapies, activate protocols are needed to more accurately assess the impact
antitumor response mechanisms, and introduce tumor-spe- of CR on breast and other cancers [237].
cific toxicities [204]. Table 1 indicates some common die-
tary interventions used in clinical and preclinical studies.
5.2 Time‑restricted feeding

5.1 Chronic calorie restriction Time-restricted feeding (TRF), the practice of restricting

time of calorie intake, rather than calories consumed, to
Chronic caloric restriction (CR), typically defined as ≥ an 8-–12-h window aligning with the circadian rhythm, is
10% reduction in caloric intake in humans and ≥ 20% an emerging dietary pattern rapidly gaining scientific and
reduction in rodents without malnutrition or the restric- cultural popularity [238]. As components of the circadian
tion of water, is an established mechanism for extension of clock interact with nutrient-sensing pathways, inconsistent
lifespan and healthspan in clinical and preclinical models eating patterns and overeating can disrupt circadian regu-
[205, 206, 222]. CR partially reverts some of the meta- lation of endocrine and nutrient metabolism [239, 240].
bolic consequences of obesity in clinical trials [223, 224]. By reducing evening energy intake and refraining from
Postmenopausal women with an increased risk of breast consuming food throughout the night, the TRF fasting
cancer show improved hormonal (bioavailable estradiol, regimen aligns meal times with the ideal postprandial hor-
testosterone, and insulin) and adipocytokine (relative monal response [241]. In a mouse model of postmenopau-
adiponectin/leptin, C-reactive protein) markers of breast sal obesity, TRF reduced body weight, improved glucose
cancer in serum and breast tissue with weight loss of more tolerance and insulin resistance, and reduced accumulation
than 10% [225]. A meta-analysis of 59 preclinical studies of fat in the liver [215]. These findings were corroborated
concluded that calorie restriction is preventive of cancer by an 8-week clinical trial of time-restricted eating in par-
development [226]. Indeed, CR reduces the incidence ticipants who were overweight and obese, where a 10-h
of several types of tumors in rodent and rhesus monkey eating window resulted in clinically meaningful reductions
models [226, 227]. CR prior to tumor induction slows in weight and improved fasting blood glucose [216].
primary tumor growth and reduces metastatic burden in There is growing evidence that circadian rhythm plays an
a preclinical model of TNBC, and 30% CR imposed at important role in cancer pathogenesis, with chronic disruptions
the time of tumor induction in this same model syner- increasing breast cancer metastasis [242, 243]. Preclinical
gized with radiation treatment to further suppress tumor models of breast cancer demonstrate promising effects, with
growth [228–230]. A 30% CR dietary regimen also miti- mice fed a high fat diet restricted to 12-h intervals having tumor
gates chemotherapy-induced inflammation and enhances burden reduced to that of control-fed mice [244].

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 Table 1  An overview of dietary interventions in human and mouse models
Diet Diet composition (humans) Diet composition (mice) Reduction in caloric intake Reduction in caloric intake Periodicity
(humans) (mice)

Calorie restriction Typical diet of participant Vitamin-fortified isonitroge- 20–25% reduction 20–40% reduction* Chronic restriction without
[205, 206] with micronutrients main- nous to ad libitum (AL) diet altered meal frequency in
tained humans;
Mice fed once daily
Cancer and Metastasis Reviews (2022) 41:607–625

Fasting Variable Standard diet No food consumption for No food consumption for Range from 12 h to weeks in
[207–209] duration of fasting period, duration of fasting period, humans; 24–60 h in mice
water allowed water provided
Fasting-mimicking diet Low protein (~ 10%), high fat Standard diet for maintenance, Day 1: ~ 1200 kcal; Days Day 1: 7.67 kJ/g (~ 50% 1–2 four-day cycles/month in
[210–212] (44–56%), high carbohy- proprietary FMD rodent 2–4: ~ 200 kcal reduction); Days 2–4: humans; 10-day breaks (or
drate (34–47%): vegetable- diet with day 1 and days 2–4 1.48 kJ/g (~ 90% reduction) complete body weight recov-
based soups, broths, and tea caloric compositions ery) between four-day cycles
in mice
Intermittent energy restric- Mediterranean-style diet on Special diet with 2 × protein, ~ 70–75% reduction for Cycles of 50% CR for Chronic restricted cycles of
tion days with no caloric reduc- vitamin, minerals, and fats 2 days/week, AL for other 3 weeks, followed by either 5:2 or every other day
[213, 214] tion for AL periods 5 days/week OR 60–70% 3 weeks of no reduction in humans; cycles of 3 weeks
reduction every other day AL, 3 weeks 50% CR in mice
Time-restricted feeding Typical diet of participant; Highly variable None required None required 12-–20-h window of fasting
[215, 216] no intervention required to every 24 h for humans and
macronutrient composition mice
Ketogenic diet High fat (75–80%), very low Customized rodent diets None required None required Chronic for humans and mice
[217, 218] carbohydrate (< 50 g/day, if containing ~ 90% fat, 9–10%
possible), moderate protein protein, and 0–1% carbohy-
(15–20%) drates
Mediterranean diet Vegetables (2–6 servings), Supplementation with None required None required Chronic for humans and mice
[219, 220] fruit (1–3 servings), grains omega-3 ethyl esters OR a
(< 8 servings), olive oil Mediterranean-style formu-
every meal (~ 37% fats, 33 g lated purified diet (highly
fiber/day) variable)
*
Periodicity of calorie intake in CR in rodents is more impactful than the actual restriction itself [221]

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616 Cancer and Metastasis Reviews (2022) 41:607–625

5.3 Fasting response and reducing hyperglycemia, often a treatment-

induced side effect [212]. Promising results from a clini-
In clinical research, fasting in humans is defined as signif- cal trial in which a majority of participants had breast
icant-to-total reprieve of caloric intake for several hours to cancer show that the FMD increases total and activated
days [208]. Due to greater feasibility and improved adher- intratumor CD8 + T cells while decreasing circulating
ence compared to CR, periodic fasting (PF) and short-term populations of immunosuppressive cells [252]. However,
fasting (STF), maintained for periods of 48–72 h in rodents the impact of FMD on long-term patient survival, or its
and 2–5 days in humans, may provide an effective compro- efficacy in patients with breast cancer and obesity, has not
mise [235]. The synergistic effect of PF in combination with been demonstrated.
cancer treatment seen in preclinical studies [245] may be
due to its effect on blood glucose levels, which are reduced
more profoundly in preclinical models of PF relative to CR 5.5 Intermittent energy restriction
[246]. Engaging in STF induces a differential stress response
between cancer cells and healthy cells, prioritizing cellular Intermittent energy restriction (IER) is a broadly-encom-
maintenance and repair in healthy cells, and exposing a vul- passing term that applies to recurring patterns of fasting,
nerability in cancer cells due to their inability to suppress either rhythmic or arhythmic, in which calorie restriction
growth-promoting pathways [246, 247]. The differential is achieved by reduction in overall eating periods rather
stress response provides a mechanism by which fasting can than meal sizes [253]. The periodicity of IER, as opposed
promote efficacy and tolerance of chemotherapy and radia- to chronic CR, has greater adherence potential while main-
tion treatments [245, 246, 248, 249]. Additionally, fasting taining comparable reductions in body weight in patients
promotes stem cell self-renewal as well as regeneration of who are overweight or obese [213, 254, 255]. Reported
the blood, nervous system, muscle, and liver [235, 250]. benefits of IER include improved glucose regulation and
In vitro data indicates TNBC sensitization to chemotherapy stress resistance as well as reduced inflammation [256].
treatment with 24-h fasting [209]. Two clinical pilot stud- IER protects against in vivo tumor development in a spon-
ies with HER2-negative breast cancer patients demonstrate taneous model of mammary carcinogenesis [257].
STF as a feasible, tolerated intervention in both trials and
a reduction in the hematological toxicity of chemotherapy
treatment in one trial [248, 251]. 5.6 Ketogenic diet

5.4 Fasting‑mimicking diet The ketogenic diet, composed of high fat, moderate

protein, and very low carbohydrates, acquired its name in
The fasting-mimicking diet (FMD) is generally very low pursuit of ketogenesis: utilizing fatty acids, metabolized
in proteins and carbohydrates, enriched in unsaturated as the ketone bodies β-hydroxybutyrate and acetone,
fats and micronutrients, and maintained for a period of rather than glucose for energy [217]. The mechanistic
days in a cyclical fashion. It is an alternative regimen to basis for a ketogenic diet reducing breast cancer incidence
a water-only fast with similar changes in stress resistance and overall disease burden lies within decreased insulin
and blood glucose but greater tolerability and adherence signaling and overall reduced inflammation seen with
[208, 250]. A combination regimen of FMD and endo- prolonged nutritional ketosis [258]. Although some data
crine-based therapies reduces IGF-1 receptor signaling, exists demonstrating the feasibility of a ketogenic diet
abates chemotherapy-induced inflammation, and enhances intervention during radiotherapy treatment for patients
tumor response to radiation in preclinical models of estro- with breast cancer, such as boasting reductions in body
gen-responsive breast cancer [232]. In vitro models of weight and fat mass [259], there is little evidence that a
TNBC responded to a FMD, including reduced circulat- ketogenic diet reduces tumor burden in patients with breast
ing glucose and IGF-1, with enhanced tumor immuno- cancer. After 12 weeks of the ketogenic diet, quality of life
genicity and improved response to chemotherapy [210]. A and physical activity scores were not improved in a study
clinical trial with 131 patients with HER2-negative breast of 80 patients with breast cancer undergoing chemotherapy
cancer demonstrated that a FMD adhered to for 3 days [260]. However, in vitro and in vivo supplementation with
prior to chemotherapy administration remained safe, effec- the ketone body β-hydroxybutyrate increases tumor growth
tive, and lowered DNA damage in T cells as one metric of in breast cancer models, presumably by providing fuel for
enhanced sensitivity to chemotherapeutic response [211]. oxidative mitochondrial metabolism [261, 262]. However,
Preclinical work has demonstrated the FMD to be effec- β-hydroxybutyrate has no effect on TNBC proliferation
tive against TNBC progression in combination with PI3K/ or response to treatment via chemotherapy or radiation
AKT/mTOR inhibitors by potentiating kinase inhibitor in vitro [263].

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Cancer and Metastasis Reviews (2022) 41:607–625 617

5.7 Mediterranean diet obese showed adherence drops of 38% for alternate-day

fasting and 29% for CR over 1 year [254]. As food intake is
Growing evidence suggests that the consumption of a neurologically regulated, several mechanisms are in place
Mediterranean dietary pattern has a protective effect to drive food consumption during periods of deprivation,
against many chronic diseases and cancers including breast causing psychological stress and negatively impacting mood
cancer [264]. The key characteristics of a Mediterranean if restriction is too severe or extends for too long [253,
diet include high consumption of fruits and vegetables 277]. Physiological changes concurrent with obesity, such
such as green leafy vegetables, legumes, nuts, and cereals; as increases in orexigenic acetyl-CoA binding protein and
moderate intake of fish and other meats; and low intake of disruption of leptin- and ghrelin-mediated appetite signaling
sweets and eggs [219]. The majority of studies examining cues, provide further barriers for adherence to restrictive
the protective effect of Mediterranean diet on cancer diets [278, 279].
progression are largely observational studies followed One solution to achieve the benefits of dietary restriction
by randomized clinical trials [265, 266]. Overall, high without encountering barriers to adherence or disturbing
adherence to a Mediterranean dietary pattern is associated energy balance are calorie restriction mimetics (CRMs).
with decreased risk of cancer mortality [267] and risk of The main objective of CRMs is to induce autophagy, which
developing breast cancer [268]. While epidemiological protects against cellular stress and damage, mobilizes
studies suggest an inverse relationship between adherence energy reserves, and removes intracellular waste or debris
to a Mediterranean dietary pattern and breast cancer [280]. By optimizing energy and redox metabolism,
risk, the evidence regarding breast cancer subtype is activating this endogenous mechanism may help cells
limited [265, 269]. The results of one systematic review avoid malignant transformation [281] or improve antitumor
suggest an inverse association between a Mediterranean immunity through autophagy induction [282].
diet pattern and breast cancer risk in postmenopausal
women, and particularly postmenopausal TNBC; however,
results are mixed [265]. Olive oil, the main dietary fat in 6 Conclusion
Mediterranean diet, has anticancer effects in experimental
studies. For example, a high extra virgin olive oil diet in Obesity promotion of the incidence and progression of
a rodent model of mammary carcinogenesis increases numerous cancers, including breast cancer, poses a significant
tumor latency and decreases tumor volume, multiplicity, public health hazard. Delineation of the mechanisms through
and incidence [270]. Additionally, olive oil consumption which obesity drives cancer progression or immune evasion
is associated with a lower odds of developing breast is critical for the development of interventions to effectively
cancer [271]. Furthermore, polyunsaturated fatty acids disrupt obesity-driven cancer with minimum toxicity. Dietary
present in a Mediterranean dietary pattern, particularly interventions remain of considerable interest due to their
omega-3 fatty acids and specifically docosahexaenoic acid co-targeting of metabolic disruptions. Breaking the obesity-
(DHA) and eicosapentaenoic (EPA), have antiproliferative breast cancer link will require interventions that limit the
effects in preclinical models of TNBC [272]. Indeed, protumor effects of obesity-associated adipose dysregulation
supplementation with EPA + DHA ethyl esters reduces and that consider other biological and genetic mediators and
mammary tumor growth in obese postmenopausal structural determinants of health disparities. Moreover, given
(ovariectomized) mice [220]. high and rising rates of obesity in many parts of the world,
emphasis should be placed on the development of safe and
5.8 Dietary considerations effective interventions that are acceptable and accessible to
all women to reduce the burden of obesity on breast cancer.
Reducing calorie intake, through fasting or calorie
restriction, prior to chemotherapy treatment reduces side
effects commonly associated with chemotherapy [273] and Author contribution Conceptualization: END, MSC, LEM, MFC,
may thereby improve quality of life for patients [251, 274, SDH; writing original draft: END, MSC; writing review and edit-
275]. However, due to heightened risk of adverse effects ing: END, MSC, LEM, MFC, SDH; funding acquisition: MSC, SDH:
supervision: SDH.
associated with weight loss and alterations to inflammatory
response that can occur with calorie restriction, widespread Funding This work was supported by R35CA197627 and BCRF-21–
clinical intervention remains challenging [247]. Additionally, 073 to SDH and T32CA057726 to MSC.
adherence to chronic CR has proven challenging for humans,
with sustainability dropping off after ~ 20 weeks for Declarations
participants who are not obese [276]. A long-term dietary
intervention study of participants who were overweight or Conflict of interest The authors declare no competing interests.

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618 Cancer and Metastasis Reviews (2022) 41:607–625

Open Access This article is licensed under a Creative Commons 18. Denkert, C., et al. (2017). Molecular alterations in triple-neg-
Attribution 4.0 International License, which permits use, sharing, ative breast cancer—The road to new treatment strategies. The
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long as you give appropriate credit to the original author(s) and the source, 19. Hales, C. M., et al. (2020). Prevalence of obesity and severe
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included in the article's Creative Commons licence, unless indicated 20. Diet, nutrition, physical activity and breast cancer. Diet, Nutri-
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by statutory regulation or exceeds the permitted use, you will need to anisms involved in obesity-related development, growth and
obtain permission directly from the copyright holder. To view a copy of progression. The Journal of Steroid Biochemistry and Molecu-
this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. lar Biology, 189, 161–170.
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