Abstract 5575: Effects of continuous combined oral contraceptives on mouse mammary gland structure and tumor progression
Authors: Esteves Evelyn , David Sherin , Bowers Dawn , MacQueen Brian , Ruszczyk Melanie , Chachad Dhruv , Shenoy Rajani Marthappa , Masso-Welch Patricia A. 
Published: May 2015

Abstract
The breast goes through cycles of cell growth, differentiation and regression with every estrous/menstrual cycle, driven by hormonal stimulation followed by hormone withdrawal. The number of cycles over a lifetime is positively associated with breast cancer risk. This increased risk may be the result of hormone-stimulated epithelial growth, inflammatory tissue remodeling processes during hormone withdrawal, or both. The use of cyclic combined oral contraceptives (cyclic COC), which incorporates a hormone withdrawal period in each cycle, has been associated with an increased risk of breast cancer, particularly in African American women, current COC users, and women who initiated COC use early in life. In contrast, the effect of extended-use (i.e., continuous) COC on breast cancer risk has not been evaluated. The purpose of the current study was to test the hypothesis that continuous exposure to COC is not associated with the increased risk observed with cyclic COC, and may even provide protection against breast cancer, by removal of the hormone withdrawal phase. Starting at day 50 of age (to mimic COC exposure in young women), BALB/C mice were fed liquid diets +/- supplementation with 0.0041 mg/kg ethinyl estradiol and 0.0185 mg/kg levonorgestrel (dose calculated by surface area conversion from the human COC dose of 20 µg ethinyl estradiol and 90 µg levonorgestrel). After 28 days, 10 mice per group were sacrificed and mammary glands dissected for whole mount and histologic analysis. An additional 20 mice per group were injected orthotopically with 10e5 syngeneic TM2H mammary epithelial tumor cells, and tracked for tumor latency, growth and tumor burden. The extended COC group showed 65% increase in mammary gland epithelial density compared to control. However, this increased epithelial density was associated with an increased alveolar branching and a decrease in carcinogen-sensitive terminal end buds. These results suggest that short term exposure to continuous COC can induce a more differentiated state in nonparous mouse mammary glands. In mice transplanted with tumor cells, the continuous COC group showed significantly increased tumor latency and decreased tumor burden, compared to controls. These results demonstrate that continuous COC administration, despite the higher levels of hormone exposure, can render the mouse mammary gland less susceptible to the growth of transplanted tumor cells. Mechanistic studies are ongoing.
Citation Format: Evelyn Esteves, Sherin David, Dawn Bowers, Brian MacQueen, Melanie Ruszczyk, Dhruv Chachad, Rajani Marthappa Shenoy, Patricia A. Masso-Welch. Effects of continuous combined oral contraceptives on mouse mammary gland structure and tumor progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5575. doi:10.1158/1538-7445.AM2014-5575