A study comparing the effects of continuous and cyclic oral contraceptive treatments on mammary gland microenvironment and tumor progression in BALB/c mice using the 4T1 transplantation model
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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 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, mice were sacrificed. Tumors in mice exposed to cyclic OC arose significantly more rapidly; continuous OC had no effect on latency. Continuous OC treated mice had the least tumor volume while the cyclic OC had the maximum tumor volume compared to control. In contrast, the continuous OC treated mice had the shortest time to sacrifice from palpation. qPCR analysis on tumors showed no difference in the levels of the inflammatory cytokines, while qPCR analysis on mammary glands right after OC treatment showed increased expression of erbB2 and some suppression of the inflammatory cytokines especially in the continuous group. Tests carried out in this study so far suggest cyclic OC treatment may have a direct effect in increasing primary tumor volume while continuous OC treatment may worsen prognosis possibly due to increased metastasis to secondary sites. Further tests need to be performed to elucidate the exact mechanism.