Many observational studies have demonstrated that increasing BMI is a risk factor for postmenopausal hormone-receptorpositive breast cancer. This is the most common subtype of breast cancer. Of note, breast cancers are considered “hormone sensitive” when they expresses the estrogen receptor (ER) and/or progesterone receptor (PR). However, gene expression profiling has allowed us to subdivide hormone-receptorpositive breast cancers into those that are likely sensitive to hormone therapies (“luminal A”) and those that are usually not (“luminal B”). Hence, hormone receptor status is an imperfect surrogate for hormone sensitivity. Of course, the absence of these receptors is very predictive of hormone insensitivity. In a meta-analysis of eight prospective cohort studies, increasing BMI was directly correlated with breast cancer risk in postmenopausal women (3). Compared to those with a BMI less than 22.5 kg/m², women with a BMI in the overweight to obese range had an increased relative risk (RR) of 1.36 to 1.62 of developing breast cancer (Table 49-1) (3).

The effect of overweight and obesity on breast cancer risk in premenopausal women is less clearly defined. More precisely, it appears likely that the influence of weight may differ based on an individual patient’s underlying risk. Cecchini et al. reported the pooled analysis of two large, randomized breast cancer prevention trials (Breast Cancer Prevention Trial [P1] and the Study of Tamoxifen and Raloxifene [STAR]), which included nearly 32,000 women at high risk of developing the disease. In comparison to premenopausal women with normal BMI, overweight (hazard ratio [HR] 1.59, 95% CI 1.05-2.42) and obese women (HR 1.70, 95% CI 1.10-2.63) had an increased risk of developing invasive breast cancer (4).

Several studies have also suggested an association between adult obesity and the development of TNBC, which lacks expression of the ER, PR, and human epidermal growth factor receptor 2 (HER2). In the Women’s Health Initiative (WHI), a longitudinal study of postmenopausal women, in which over 5,000 invasive breast cancers were diagnosed, the highest quartile of BMI (31.5 or higher) was associated with a 1.39-fold (95% CI 1.22-1.58) increase in the risk of ER-positive breast cancer when compared to women with a BMI in the lowest quartile (less than 23.75) but a similar magnitude of risk of TNBC was also seen (HR 1.35, 95% CI 0.92-1.99), although this latter result was not statistically significant (5).

Studies examining the prognostic effect of overweight or obesity after a breast cancer diagnosis have consistently demonstrated poorer clinical outcomes for women with
an elevated BMI. In a recent meta-analysis, Protani and colleagues examined 43 studies with sample sizes ranging from 100 to more than 420,000, and included women diagnosed with breast cancer from 1963 to 2005. The authors demonstrated that obese women consistently experienced higher breast cancer-specific (HR 1.33, 95% CI 1.19-1.50) and allcause mortality (HR 1.33, 95% CI 1.21-1.47) in comparison to their nonobese counterparts (6). Obesity has also been associated with several other poor clinical outcomes including increased risk of contralateral breast cancer and second primary breast cancers (7).

Obesity is associated with insulin resistance, characterized by impaired glucose tolerance and elevated systemic levels of insulin and insulin-like growth factor-1 (IGF-1), which have both been associated with breast cancer risk and worse prognosis (9). In a cohort of 512 patients with early-stage breast cancer, elevated fasting insulin levels were associated with both distant recurrence (HR 2.0, 95%
CI 1.2-3.3) and all-cause mortality (HR 3.1, 95% CI 1.7-5.7) (9). It is theorized that insulin mediates breast carcinogenesis by stimulating signaling through activation of insulin/IGF-1 receptors that can be overexpressed on human breast cancer cells. Downstream activation of the Ras-Raf-MAPK and PI3K/Akt pathways ultimately leads to tumor cell proliferation and inhibition of apoptosis. Additionally, IGF-1 and insulin have been shown to stimulate aromatase activity in adipose tissue. Moreover, increasing insulin levels can affect sex hormone biosynthesis leading to increased androgen production by the ovaries and decreased hepatic production of sex hormone-binding globulin (SHBG) that normally antagonizes some negative effects of circulating estrogens.

Adipokines, a group of proteins synthesized and secreted from adipose tissue, are also implicated in the interaction between obesity and breast cancer. Decreased serum adiponectin and elevated leptin levels have been associated with obesity and type 2 diabetes mellitus. Similar disturbances in these adipokines have also been associated with increased breast cancer risk (10) and worse prognosis (11). Although the mechanisms underlying these phenomena are incompletely understood, adiponectin is thought to exert its effects through the activation of multiple downstream signaling pathways including AMPK, PI3K/mTOR, and the transcription factor, nuclear factor-kappaB (NF-κB), which have also been implicated in breast cancer development (12). In addition, adiponectin has been shown to inhibit the growth of multiple breast cancer cell lines (13).

In contrast, leptin is thought to affect different aspects of breast tumorigenesis such as cell growth, angiogenesis, and metastasis and is to known to act mainly through activation of the JAK/STAT, MAPK/ERK, and PI3K/Akt signaling pathways leading to increased cell migration, invasion, and cell survival. Leptin-induced proliferation has been associated with overexpression of c-myc and cyclin D1which are important in cell cycle regulation (12). Finally, leptin has also been reported to have both proinflammatory and angiogenic properties, which may be important for breast carcinogenesis.

Obesity causes chronic subclinical inflammation in adipose tissue (14). In obese women, increased levels of proinflammatory mediators such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are commonly found in the circulation and may contribute to breast cancer progression and mortality. Interactions between adipocytes and immune cells promote this proinflammatory response through tolllike receptor- (TLR)-mediated signaling pathways and the activation of NF-κB. In mouse models of obesity and in overweight and obese humans, macrophages infiltrate visceral and subcutaneous adipose tissue and form characteristic crown-like structures (CLS) around dead adipocytes. In both dietary and genetic models of obesity, CLS occur in the adipose tissue of the mouse mammary gland as well as in visceral fat (15). Similarly, in women undergoing mastectomy, the presence of CLS of the breast (CLS-B) was associated with increased BMI. Importantly, the presence of CLS-B is associated with NF-κB-dependent upregulation of multiple proinflammatory mediators such as interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and TNF-α, which leads to increased transcription of CYP19, the gene encoding aromatase (16, 17). These elevated levels of proinflammatory molecules and aromatase expression and activity are paralleled by upregulation of PR, an ER target gene. Aromatase activity correlates more strongly with the CLS-B index (p = .88, p < .001), a marker of extent of inflammation, than with BMI (p = .5, p = .02). This finding underscores the fact that obesity-related inflammatory mediators are critical for the induction of aromatase. Collectively, these results establish the existence of an obesity-inflammation-aromatase axis in breast tissue, which is likely to be one mechanism by which obesity influences breast carcinogenesis.