Effects of Continuous versus Cyclic Oral Contraceptives on Mammary Tumor Growth

描述（由申请人提供）：毫无疑问，乳腺癌易感性与终生暴露于雌激素和黄体酮（E+P）密切相关。使用广泛使用的激素替代疗法（HRT）延长E+P暴露会增加绝经后妇女患乳腺癌的风险。口服避孕药（OC）的使用方式与激素替代疗法类似，是广泛使用的激素疗法的一个例子，有可能影响大量人群的乳腺癌化学预防。与激素替代疗法不同的是，口服避孕药在一生中使用的时间很长，有时早在青春期就开始使用，以控制生育能力和月经副作用。随着最近持续给药方案的出现，消除了激素停药期，妇女可以选择接受数月或数年的持续激素暴露，而不会像通常伴随周期性给药方案那样导致乳房或子宫的重塑。基于口服避孕药消除月经和伴随的副作用的能力，这并不奇怪，在美国约21%的成年女性目前使用口服避孕药已经开始转向持续治疗方案。因此，这是至关重要的，

DESCRIPTION (provided by applicant): There is no question that breast cancer susceptibility is strongly correlated with lifelong exposure to estrogen and progesterone (E+P). Extension of E+P exposure using a widely employed hormone replacement therapy (HRT) increased breast cancer risk in postmenopausal women. Oral contraceptive (OC) use, in a manner similar to HRT, is an example of a widely used hormonal regimen with the potential to impact breast cancer chemoprevention in a huge population. Unlike HRT, OC are used over a large expanse of a lifetime, sometimes initiated as early as puberty, to control fertility and menstrual side effects. With the recent advent of the continuous dosing regimen, in which the hormone withdrawal period is eliminated, women have the option to undergo months or years of continuous hormonal exposure with no remodeling of the breast or uterus that normally accompanies cyclic dosing regimens. Based on the ability of OC to eliminate menstruation and accompanying side effects, it is not surprising that many of the ~21% of adult women in the US who are current users of OC have begun to shift to a continuous regimen. It is critical, therefore, to determine whether continuous exposure to OC carries a significant risk to increase breast cancer. Although we might predict an increased risk (based on the risks from HRT), cycling women experience two types of tissue responses that do not occur in menopausal women: (i) cycles of epithelial and stromal vascular (angiogenic) proliferation in response to hormones, and (ii) cycles of apoptosis and glandular and stromal vascular regression. These two observations suggest two alternate potential outcomes of continuous OC dosing: (i) If hormone-dependent epithelial and angiogenic proliferation is critical to breast cancer risk, we predict that continuos OC use will increase breast cancer risk; (ii) Alternately, if the glandular and stromal vascular regression and remodeling in response to hormone withdrawal contribute to breast cancer risk (as has been proposed for hormone withdrawal during post-lactational involution), then continuous dosing may decrease breast cancer risk. This proposal is designed to test these two alternate hypotheses. Aim 1 will compare the ability of cyclic (3 days on, 1 day off) versus continuous dosing +/- OC to alter spontaneous tumor development, progression, and metastases in the FVB-MMTV-Her-2/Neu model of spontaneous mammary tumorigenesis. Aim 2 will compare the ability of cyclic versus continuous dosing +/- OC to alter the mammary tumor growth using the TM2H transplantable mouse mammary tumor cell line. Mammary tumors from different treatment groups will be compared for alterations in expression of ER, PR, and Her2/Neu, vascularity and proliferative and apoptotic indices. The primary outcome of these studies is to define the effects of continuous dosing of OC on primary and metastatic mammary tumor growth in two distinct mouse mammary tumor models, relative to no OC or cyclic dosing of OC.