Effects of Continuous versus Cyclic Oral Contraceptives on 4T1 Mammary Tumor Growth and Progression
Sherin David, Evelyn Esteves-Natal, Dawn M. Bowers-Rowland, Brian MacQueen, Akinsola Oyelakin, Sailee Rassam, Yen-Chan Lim, Anis Mohd, Patricia Masso-Welch
Cyclic oral contraceptives (OC), although effective at preventing uterine and ovarian cancers, increase breast cancer risk. However, the effects of extended use (continuous) OC on breast cancer risk are unknown. We hypothesize that the continuous OC regimen may be protective, due to the lack of a hormonal withdrawal phase, resulting in a continuous mammary gland resting state with no cyclic inflammatory tissue remodeling. In order to test the hypothesis that continuous OC are protective, BALB/c mice were exposed to the human equivalent dose of OC (ethinyl estradiol and levonorgestrel) using a continuous or cyclic regimen for 28 days; the cyclic regimen was three days of hormone exposure, followed by one day withdrawal, to model the murine 4 day estrous cycle. After 28 days of OC exposure, 105 4T1 syngeneic breast cancer cells were injected into mammary gland number four. Mice were fed, weighed and palpated daily and tracked for tumor latency, tumor burden, and tumor growth rate. After tumors reached 1 cm in longest diameter, or mice appeared moribund, primary tumors were paraffin embedded for histologic analysis of primary tumor histopathology (nuclear grade, glandular differentiation and mitotic index) and analysis of metastases for frequency and histopathology. Tumors in mice exposed to cyclic OC arose ~ 30 percent more rapidly more rapidly; continuous OC had no effect on latency. Continuous OC reduced primary tumor volume by 34 percent, while cyclic OC increased volume by 18 percent, compared to control. Time from tumor injection to sacrifice was unchanged by OC exposure. Additional analysis is ongoing.