Abstract 4176: Leptin mediates the anti-breast cancer effects of environmental enrichment

Abstract

Abstract Obesity affects 35% of U.S. adults and is a leading risk factor for breast cancer in postmenopausal women, but worsens prognosis regardless of menopausal status. Importantly, progression to obesity can largely be slowed or reversed with aggressive lifestyle changes, thus also having the potential to mitigate cancer onset. A mouse model of environmental enrichment (EE) to improve motosensory, cognitive, and social stimulation by increasing physical engagement and social interaction triggers vast improvements in overall health. These include reducing adiposity, promoting the white to brown fat transition, mitigating diet-induced obesity (DIO), and decreasing progression of multiple cancer types including colon cancer and melanoma. We have elucidated the primary mechanism of the EE-induced phenotype to be the activation of the hypothalamic-sympathoneural-adipocyte (HSA) axis, a specific neuroendocrine route in which the brain communicates with adipose tissue. These benefits may also be partially attributable to the sharp drop in serum leptin levels following EE which has been implicated in diminishing tumorigenesis, invasiveness, and metastasis. Here we investigated the effects of EE on breast tumorigenesis in all body mass states and menopause-associated hormone conditions. Our preliminary studies showed that EE delayed the cancer onset in the MMTV-PyMT spontaneous mouse model of breast cancer. In addition the role of leptin signaling in the EE-induced effects on breast tumorigenesis was investigated by utilizing obese models with varied leptin signaling including leptin receptor-defective db/db mice that express extremely high levels of leptin, leptin-defective ob/ob mice that do not express leptin but are leptin-sensitive, and a diet-induced obesity (DIO) model with elevated leptin but intact leptin signaling. These obese mice were housed in EE or control housing until significantly attenuated weight gain was observed followed by implantation of primary PyMT-derived mammary tumor cells. EE was highly effective at reducing adiposity in each of these obesity models, regardless of leptin signaling. However, the effects of EE on mammary tumor progression were dependent on leptin signaling. EE decreased leptin level and inhibited mammary tumor growth in DIO mice. In contrast EE failed to attenuate tumor progression in ob/ob mice in the absence of leptin, suggesting that leptin is a key mediator of the EE anti-cancer effects on breast cancer. The elucidation of mechanisms of EE and the HSA axis-induced improvement in overall health will provide effective prevention as well as therapeutic strategies for metabolic syndromes and associated cancer types. Citation Format: Grant Foglesong, Wei Haung, Lei Cao. Leptin mediates the anti-breast cancer effects of environmental enrichment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4176.