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25 June 2020

Obesity and Breast Cancer: A Case of Inflamed Adipose Tissue

and
1
Department of Pathology, Immunology and Laboratory Medicine, Gainesville, FL 32610, USA
2
University of Florida Health Cancer Center, Gainesville, FL 32610, USA
*
Author to whom correspondence should be addressed.
Cancers2020, 12(6), 1686;https://doi.org/10.3390/cancers12061686
This article belongs to the Special Issue How Does Obesity Cause Cancer?
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Abstract

Obesity is associated with an increased risk of estrogen receptor-positive breast cancer in postmenopausal women and a worse prognosis for all major breast cancer subtypes regardless of menopausal status. While the link between obesity and the pathogenesis of breast cancer is clear, the molecular mechanism of this association is not completely understood due to the complexity of both obesity and breast cancer. The aim of this review is to highlight the association between obesity and breast cancer and discuss the literature, which indicates that this association is due to chronic adipose tissue inflammation. We will discuss the epidemiological data for the association between breast cancer incidence and progression as well as the potential molecular mechanisms for this association. We will focus on the role of inflammation within the adipose tissue during the pathogenesis of breast cancer. A better understanding of how obesity and adipose tissue inflammation affects the pathogenesis of breast cancer will lead to new strategies to reduce breast cancer risk and improve patient outcomes for obese patients.

1. The Statistics and Co-Morbidities of Obesity

Obesity is a condition of having excess body fat that poses a health risk. It is generally defined as having a body mass index (BMI)—an indicator of body fatness determined by dividing the weight of an individual by the square of their height—of ≥30, whereas BMIs from 18.5 to 24.9 are normal weight and BMIs within the range of ≥25 to <30 are considered overweight [1]. Obesity is an increasing public health crisis, as the number of obese adults in the world has approximately doubled since 1980, with an estimated 1.9 billion people or more than 1/3 of the population being overweight or obese [1]. Obesity is a complex multifactorial condition that systemically affects the body and is caused when energy intake is greater than energy expenditure. The increase in the prevalence of obesity over the last 40 years is influenced by many things, including diet, environment, socioeconomic factors, and decreased physical activity due to modern lifestyles [2,3,4].
Obesity is particularly prevalent in western countries, with the American and European regions having the highest prevalence of obesity. In the U.S. and Europe, 28.3% and 22.9% of adults were obese in 2015, a 2.2 and 1.6 fold increase, respectively, since 1980 [1]. This represents both a major public health and economic problem. The public health problem arises from the association of obesity with the increased risk of several chronic health problems, including diabetes, cardiovascular disease, liver disease, and several types of cancer [5,6]. Studies have indicated that every 5 point increase in BMI over 25 results in a 29% increase in overall mortality, a 210% increase in diabetes-associated mortality, and a 41% increase in mortality related to the cardiovascular system [7,8]. Obesity greatly increases the risk of non-alcoholic fatty liver disease (NAFLD)—a chronic liver condition that can lead to nonalcoholic steatohepatitis (NASH) and is one of the most common indicators of transplantation need in Western countries [9]. Histological analyses of liver samples from biopsies, donors, and cadavers have shown that 15% of non-obese people had NAFLD, while 65% of obese individuals and 85% of morbidly obese people (BMI > 40) had NAFLD [10,11,12,13,14]. Obesity is the leading risk factor for the development of type 2 diabetes mellitus [15]. Obesity is associated with both an increased risk and worse outcome for several types of cancer, including liver, gastrointestinal, esophageal, ovarian, and breast cancers [16]. Approximately 3.5% of cancer in men and 9.5% in women are due to obesity, with 14.2% and 19.8% of cancer-related mortality attributed to obesity in men and women, respectively [17,18]. A large meta-analysis by Larsson S.C. and Wolk A., which included more than 7 million people, found that there was a 24% increase in the risk of liver cancer for every 5-point increase in BMI. This study also found that the relative risk of liver cancer is 17% in overweight individuals and 89% in obese individuals [19]. Several studies have shown that obesity, as indicated by BMI, is associated with an increased risk of colon cancer [20,21,22], though other measurements of obesity, such as waist circumference or waist-to-hip ratio, are better predictors of colon cancer risk [23]. A meta-analysis of 19 prospective studies found that a larger waist circumference and waist-to-hip ratio was associated with a relative risk of colon cancer of 1.53 and 1.39, respectively [24]. In melanoma, while the association between obesity and cancer risk is not as clear [25,26,27,28,29,30], some studies have shown that obesity may be associated with disease progression and resistance to therapy [31,32,33,34]. Conversely, some studies have shown that obese patients may respond better to immunotherapies [35,36].
The health risk associated with obesity leads to increased health care costs. This, along with lost productivity due to these chronic health problems, contributes to the economic impact of obesity [37,38]. In 2008, the estimated health care cost associated with obesity in the U.S. was $147 billion, and the annual cost of lost productivity is estimated to be between $3.4 and $6.4 billion [39,40].

2. Obesity and Breast Cancer

There have been numerous epidemiological studies and meta-analyses to demonstrate that obesity is associated with both an increased risk of estrogen-receptor (ER)-positive breast cancer in post-menopausal women and worse clinical outcomes independent of menopause status relative to their normal-weight counterparts. Here, we will briefly cover this association, as it has been extensively reviewed [6,41,42]. Several large studies, including the Nurses’ Health Study of more than 87,000 women and the European Prospective Investigation into Cancer (EPIC) study of about 250,000 post-menopausal women, have shown that increased body weight is associated with an increased risk of developing ER-positive breast cancer in postmenopausal women [43,44]. Several meta-analyses and prospective studies have also been performed and support the above conclusion [45,46,47,48]. There are inconsistent results between obesity and breast cancer risk in premenopausal women. In one study, obesity was associated with a decreased risk of developing ER-positive breast cancer in pre-menopausal women, while being associated with a higher risk in post-menopausal women. The authors found no correlation between obesity and ER-negative breast cancer [49]. However, a meta-analysis has indicated that obese pre-menopausal women had a higher risk of developing triple negative breast cancer (TNBC) [50]. This is supported by other studies indicating that obese premenopausal patients are more likely to have TNBC [51,52]. There are also reports showing an association between obesity and the risk of inflammatory breast cancer regardless of menopausal and ER status [53,54,55].
Apart from the increased risk of developing breast cancer, several studies have shown that obesity is associated with worse outcomes for breast cancer patients irrelevant of subtypes. Several meta-analyses have been performed and provide strong evidence for the association between obesity and increased breast cancer mortality. One analysis of 43 studies found a 33% increased rate of death in obese patients [56]. Another meta-analysis of 82 studies found an estimated increased risk of all-cause mortality and breast cancer-specific mortality of 41% and 35%, respectively. This increase in mortality was independent of menopausal and ER status [57]. A large prospective cohort study of breast cancer patients in Denmark showed that obesity was associated with an increased risk of distant recurrence after 5–10 years, with a hazard ratio of 1.42 (95% confidence interval (CI), 1.17 to 1.73) and 1.46 (95% CI, 1.11 to 1.92) for overweight and obese patients [58]. Several other studies have found similar results showing the correlation between obesity and distant breast cancer recurrence [59,60,61,62]. Obesity has also been shown to be associated with an increased risk of developing a secondary malignancy—both at the contralateral breast or at other sites [63].
Obesity also affects other aspects of breast cancer, including diagnosis, treatment, and metastasis. A few studies have shown a correlation between obesity and higher Tumor Node Metastastis (TNM) stage with increased lymph node involvement at time of diagnosis [58,64]. However, this association may be due to diagnostic difficulties and/or reduced adherence to mammographic screening recommendations in obese women [65,66,67]. Obesity is also associated with an increased risk of complications following surgical treatment of breast cancer [42,68,69]. Other studies have shown that obesity is associated with a reduced response to therapeutic treatments, though this may be related to dose-limiting toxicities and undertreatment in obese patients [70,71,72]. However, some studies have suggested a molecular link between obesity and the resistance to these therapies, particularly in relation to adipocytes [73,74,75,76,77]. Obesity has also been linked to increased distal and/or lymph node metastasis [78,79,80,81]. More studies and meta-analyses are still needed to establish the link between obesity and breast cancer progression, response to therapy, and metastasis.
A summary of some of these studies can be found in Table 1.
Table 1. Epidemiological studies of obesity and breast cancer. Abbreviations: RR, relative risk; HR, hazard ratio; OR, odds ratio; BC, breast cancer; CI, confidence interval.

4. Adipose Tissue Inflammation and Breast Cancer in Non-Obese Women

The evidence suggests that obesity-associated chronic inflammation in adipose tissue is, at least in part, driving the correlation between obesity and breast cancer. Given that adipocytes are an important component of the breast cancer tumor microenvironment [82], it is reasonable to speculate whether obesity-associated inflammation can promote breast cancer in non-obese women, or if it is specific to obesity. The idea that adipose tissue inflammation may promote obesity-related co-morbid conditions independently of obesity is supported by studies showing that adipose tissue inflammation is correlated with insulin resistance, metabolic syndrome, and type 2 diabetes in normal weight individuals [158,159,160].
In order to study the association between adipose tissue inflammation and breast cancer, markers for inflamed adipose tissue need to be identified. As stated previously, obesity leads to adipocyte hypertrophy, cell death, the recruitment of macrophages, and the formation of CLS (Figure 1). The appearance of CLS in adipose tissue is considered a histological marker of inflammation. Indeed, studies have shown that the abundance of CLS is elevated in the adipose tissue of obese patients and animals and is an indication of the level of macrophage infiltration, inflammatory cytokines, and aromatase expression [134,140,161]. Moreover, the abundance of CLS in adipose tissue is associated with insulin levels, insulin resistance, and type 2 diabetes [162]. However, while CLSs are more prevalent in obese patients, they do occur in non-obese patients. One small study found that while CLSs are found in 75% of obese patients, they are also found in 8% of normal weight patients [140]. This is supported by other studies finding similar rates of CLS in adipose tissue in obese and non-obese patients [159,163].
There are a few studies showing that the presence of CLS in mammary adipose tissue may increase the risk of breast cancer independently of obesity. One study looked for CLS in mammary adipose tissue from benign biopsies and found that a high CLS count was associated with an increased risk of developing breast cancer after adjusting for BMI, indicating that a high CLS count may be an independent marker of breast cancer risk [164]. In another study, Iyengar, NM. et al. evaluated tissues from women undergoing mastectomy and found that CLSs are associated with elevated insulin levels, CRP, and IL-6. Furthermore, a high CLS count is associated with a shorter distant relapse-free survival (HR 1.83; 95% CI, 1.07–3.13) after adjusting for BMI [165]. In a similar study, Iyengar, NM. et al. looked at samples from 72 normal weight women undergoing mastectomy for breast cancer risk reduction and found that CLS abundance is correlated with higher levels of aromatase expression, leptin, insulin, and CRP [159]. These studies support that adipose tissue inflammation, as evidenced by the presence of CLS, may increase the risk of breast cancer and promote breast cancer progression independently of obesity.

5. Conclusions

There is sufficient evidence to support the idea that obesity is a risk factor for the development of breast cancer and is associated with increased mortality. The association between obesity and breast cancer outcomes may be because obese patients tend to have a higher TNM stage when diagnosed, though some studies have shown that the correlation between obesity and mortality is independent of stage [58,64,80]. This correlation between obesity and breast cancer mortality warrants the development of better strategies for treating obese patients. Some of the correlation with poor outcome may be related to the suboptimal dosing of chemotherapies in obese patients due to dose-limiting toxicities. New guidelines recommend using the full dose of chemotherapy based on actual body weight in obese patients, because studies have shown that this does not increase treatment-related toxicity [166,167]. Other studies have looked at the use of metformin in treating obese patients as it has been shown to reduce the risk of several cancers, including breast cancer [168,169,170]. Interestingly, some studies have shown that obese patients may respond better to immunotherapies [35,36].
Given the evidence that adipose tissue and in particular adipose tissue inflammation is a major driver of the association between obesity and breast cancer, targeting adipocyte-secreted factors may be a viable therapeutic approach for improving outcomes for obese patients. Several agents targeting the chemokines and cytokines secreted by adipocytes which are elevated by obesity have been used in clinical and preclinical studies. These include Cenicriviroc, an inhibitor of C-C motif Chemokine Receptor 2 (CCR2), the receptor for C-C motif Chemokine Ligand 2 (CCL2), which is important in the recruitment of macrophages to obese adipose tissue [171,172]; Tocilizumab, an IL-6 receptor antibody [173]; Canakinumab, an IL-1β antibody [174]; and Infliximab, a TNFα antibody [175]. We recently showed that obesity-associated inflammation promotes the upregulation of ANGPTL4 in adipocytes, which drives breast cancer angiogenesis and progression. As such, we have developed antibodies against human ANGPTL4 that inhibit ANGPTL4-induced angiogenesis [92]. Therapies which target adipocyte-secreted factors warrant further investigation for treating obese breast cancer patients.
Another possibility is to treat the obesity itself, and there are a few clinical studies looking at the effect of weight loss on breast cancer, including the Breast Cancer WEight Loss (BWEL) study (NCT0270826). The effect of weight loss as a method for lowering breast cancer risk is supported by a few studies, including a large prospective study that found that sustained weight loss in women over 50 is associated with a reduced risk of developing breast cancer [176]. Other studies looking at obese patients who underwent bariatric surgery for weight loss have shown that they have a reduced risk of several types of cancer, including breast cancer [177,178]. Apart from potentially reducing the risk and/or progression of breast cancer, several studies have shown that weight loss can improve the quality of life of breast cancer patients [179,180]. While more studies need to be performed to further support these findings, weight loss intervention may be beneficial for obese breast cancer patients.
Many studies support that obesity-associated inflammation—particularly in mammary adipose tissue—is a major contributor to this association. Interestingly, some studies suggest that mammary adipose tissue inflammation may be a risk factor for breast cancer in normal weight individuals [159,164,165]. There are people that fall into a category referred to as metabolically obese with a normal weight. Though having a BMI in the normal range (18.5–24.9), these individuals tend to have higher adiposity, increased adipose tissue inflammation, and are at a higher risk of developing metabolic syndrome and cardiovascular diseases [158,160,181,182]. It is possible that metabolically obese but normal weight people are also at a higher risk of developing obesity-related cancers including breast cancer, though more studies need to be conducted to support this connection. As obesity and many of the inflammatory cytokines upregulated in obese adipose tissue are positively correlated with breast cancer mortality [152,153], studies should be performed to see if adipose tissue inflammation is a prognostic indicator in both obese and normal weight patients. In summary, an increasing body of evidence strongly supports that obesity-associated inflammation in mammary adipose tissue drives the correlation between obesity and breast cancer risk and poor outcomes. Furthermore, adipose tissue inflammation may promote breast cancer independently of obesity.

Author Contributions

R.K. and W.Z. conceived, wrote, and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by NIH grants CA200673 (W.Z.) CA2033834 (W.Z.), K22 CA229595 (R.K) and DOD/CDMRP grant BC180227 (W.Z,) and an endowment from the James Robert Spencer Family Cancer Research Fund (W.Z.) R.K. and W.Z. are also supported by internal funding from the Department of Pathology, Immunology, and Laboratory Medicine at the University of Florida, the University of Florida Cancer Center and the University of Florida College of Medicine.

Conflicts of Interest

The authors declare no conflict of interest.

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