Obesity and Overfeeding Affecting Both Tumor and Systemic Metabolism Activates the Progesterone Receptor to Contribute to Postmenopausal Breast Cancer

Abstract

Obese postmenopausal women have increased risk of breast cancers with poorer clinical outcomes than their lean counterparts. However, the mechanisms underlying these associations are poorly understood. Rodent model studies have recently identified a period of vulnerability for mammary cancer promotion, which emerges during weight gain after the loss of ovarian function (surgical ovariectomy; OVX). Thus, a period of transient weight-gain may provide a lifecycle-specific opportunity to prevent or treat postmenopausal breast cancer. We hypothesized that a combination of impaired metabolic regulation in obese animals prior to OVX plus an OVX-induced positive energy imbalance might cooperate to drive tumor growth and progression. To determine if lean and obese rodents differ in their metabolic response to OVX-induced weight gain, and whether this difference affects later mammary tumor metabolism, we performed a nutrient tracer study during the menopausal window of vulnerability. Lean animals preferentially deposited excess nutrients to mammary and peripheral tissues rather than to the adjacent tumors. Conversely, obese animals deposited excess nutrients into the tumors themselves. Notably, tumors from obese animals also displayed increased expression of the progesterone receptor (PR). Elevated PR expression positively correlated with tumor expression of glycolytic and lipogenic enzymes, glucose uptake and proliferation markers. Treatment with the anti-diabetic drug metformin during ovariectomy-induced weight gain caused tumor regression and downregulation of PR expression in tumors. Clinically, expression array analysis of breast tumors from postmenopausal women revealed that PR expression correlated with a similar pattern of metabolic upregulation, supporting the notion that PR+ tumors have enhanced metabolic capacity after menopause. Our findings have potential explanative power in understanding why obese, postmenopausal women display an increased risk of breast cancer.

FGFR1 underlies obesity-associated progression of estrogen receptor–positive breast cancer after estrogen deprivation

“…Recently, FGFR1 was reported to interact with ER in the cytoplasm and nucleus of endocrine-resistant breast cancer cells, suggesting that ER remains functional through growth factor pathway activation, despite estrogen deprivation (14). Taken together, these observations support a dual-requirement hypothesis that we have previously presented (38,47), in which metabolic impairment associated with obesity converges with a positive energy balance following estrogen deprivation to form a tumor-promoting environment (Figure 7). To tackle this problem clinically, it may only be necessary to improve metabolic function, either pharmacologically or through exercise, or to prevent EWD-induced weight gain.…”

Elovl6 is a poor prognostic predictor in breast cancer

“…A rodent model study demonstrated that obese animals deposited excess nutrients into tumors, and increased expression of PR was positively correlated with glycolytic and lipogenic enzymes from tumors (15). In a retrospective study in Asia, it was observed that obese women experience more advanced disease with higher axillary lymph node ratio and higher stage at diagnosis (16).…”

“…The mechanism underlying the association between increased incidences of breast cancer and obesity in women remains poorly understood, but a growing body of evidence suggests that insulin resistance, chronic inflammation, estrogen and adipokine interaction may be involved (14). An expression array analysis of breast tumor tissues from postmenopausal women demonstrated that progesterone receptor (PR) expression correlated with metabolic upregulation of glucolysis and lipogenesis (15). Furthermore, it has been identified that obesity is correlated with estrogen receptor (ER) and PR expression, thus supporting their underlying associations (16).…”

Targeting breast cancer through its microenvironment: Current status of preclinical and clinical research in finding relevant targets

“…Clinical trials are ongoing to study the anti-cancer effect of dietary fat reduction and physical exercise (Table 1). Chronic inflammation is related to the development of various cancer types (Giles et al, 2012). In two case-control studies with in total almost 2000 post-menopausal women, systemic levels of the aspecific inflammatory marker C-reactive protein or soluble tumor necrosis factor receptor 2 were associated with overweight and increased breast cancer risk (Gross et al, 2013;Ollberding et al, 2013).…”

“…Metformin indeed diminishes the growth of breast cancer cells in vitro (Zakikhani et al, 2006). In obese rats in which mammary tumor growth was induced by 1-methyl-1-nitrosourea injection, metformin treatment reduced tumor burden (Giles et al, 2012). Insulin and hyperinsulinemia can also promote tumorigenesis indirectly by influencing the levels of other modulators, such as IGFs, sex hormones, inflammatory processes and adipokines (Jalving et al, 2010).…”