Obesity and postmenopausal breast cancer : determining the role of local aromatase expression
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Obesity is associated with a worse breast cancer prognosis, particularly in estrogen receptor alpha (ER alpha) positive, postmenopausal patients. It has also been correlated with elevated levels of inflammation, which can stimulate adipose tissue aromatase expression and subsequent estrogen production. Given that obese patients have a lower response rate to aromatase inhibitor treatment and greater mammary tissue aromatase levels, it was hypothesized that obesity promotes ER alpha positive postmenopausal breast cancer progression in part via an inflammation-induced increase in mammary tissue aromatase expression and ER alpha activity. These studies utilized an in vitro model of obesity in which cultured cells were exposed to postmenopausal breast cancer patients’ serum samples, pooled by body mass index category (Obese (OB): ≥30.0 kg/m2; Normal weight (N): 18.5-24.9 kg/m2). OB versus N patient sera induced greater breast cancer cell (BCC) aromatase expression, as well as higher ER alpha activity and cell viability in the presence of testosterone, the substrate for aromatase. Pre-adipocytes exposed to OB versus N patient sera also indirectly stimulated greater BCC aromatase expression, ER alpha activity, and viability. A retrospective review of breast cancer patient data demonstrated that daily use of non-steroidal anti-inflammatory drugs, which inhibit cyclooxygenase-2 (COX-2) activity, is associated with reduced ER alpha positive breast cancer recurrence in obese and overweight women. The mechanisms mediating this effect were examined using the same in vitro model. Exposure to OB versus N patient sera stimulated greater macrophage and BCC COX-2 expression and prostaglandin E2 production, leading to enhanced pre-adipocyte aromatase expression. These OB patient sera-induced effects were further linked with greater BCC ER alpha activity, proliferation, and migration in the presence of testosterone, and these differences were eliminated or reduced with aromatase inhibition. Based on these findings, prospective studies designed to examine the clinical benefit of NSAID use in obese ER alpha positive postmenopausal breast cancer patients are warranted. Additional obesity-associated mechanisms that may also promote breast cancer progression were also explored, including enhanced cross-talk between non-genomic ER alpha and growth factor signaling pathways, reduced estrogen receptor beta expression, and resistance to chemotherapy. Finally, the impact of obesity on tumor incidence and characteristics in the MMTV-Wnt1 mouse model of mammary carcinogenesis was explored.