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

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 life cycle–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 imbalancemight cooperate to drive tumor growth and progression. To determine if lean and obese rodents differ in theirmetabolic response toOVX-inducedweight gain, andwhether 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 tomammary 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 proliferationmarkers. Treatment with the antidiabetic drugmetformin 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 PRþ 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. Cancer Res; 72(24); 6490–501. 2012 AACR. Introduction Obesity increases incidence, progression, and mortality from breast cancer (1), with the adverse effects of obesity primarily observed in postmenopausal woman (1, 2). After menopause, adipose tissue becomes a significant site for the production of estrogens,whichmay lead to tumorpromotion inobesewomen. Supporting this assertion, some studies indicate that circulating estrogens are higher with increasing weight (3) and obesity generally promotes hormone-dependent tumors (4, 5). A recent study has also shown that adipose tissue aromatase activity increases with adiposity (6). Despite this evidence, local levels of estrogens in breast tissue of postmenopausal women were unaffectedbyobesity (7). Furthermore, a decrease inbothbreast cancer risk and mortality was recently reported in postmenopausal women receiving oral estrogens, independent of body mass index (BMI; ref. 8). Thus, while estrogen and obesity clearly interact to influence breast cancer, our understanding of this complex relationship remains incomplete. Obesity is associatedwith impairedwhole bodymetabolism, including a decreased ability to quickly clear and store excess calories during periods of overfeeding (9, 10). Weight gain is very common during menopause, in part, because loss of ovarian estrogen reduces leptin sensitivity in the hypothalamus, thus promoting overfeeding (11). Unless proactive measures are made to replace the loss of ovarian estrogen, restrict energy intake, and/or increase energy expenditure postmenopause, weight gain ensues (12). Calorie restriction and/or weight loss reportedly reduces tumorigenesis and the mitogenic potential of serum (13–16). Conversely, the overfeeding and weight gain associated with menopause is anticipated to create a host environment rich in circulating excess nutrients (particularly glucose and fatty acids), and growth factors [insulin, insulin-like growth factor-I (IGF-I), EGF, and leptin], Authors' Affiliations: Anschutz Health and Wellness Center; Department of Pathology; Division of Endocrinology, Metabolism and Diabetes, and Division of Medical Oncology in the Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Corresponding Author: Paul MacLean, University of Colorado Anschutz MedicalCampus, 12800East 19thAvenue, Aurora, CO80045. Phone: 303724-3030; Fax: 303-724-3031; E-mail: [email protected] doi: 10.1158/0008-5472.CAN-12-1653 2012 American Association for Cancer Research. Cancer Research Cancer Res; 72(24) December 15, 2012 6490 on April 14, 2017. © 2012 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Published OnlineFirst December 7, 2012; DOI: 10.1158/0008-5472.CAN-12-1653