Effects of Continuous versus Cyclic Oral Contraceptives on Mammary Tumor Growth

描述(由申请人提供)：毫无疑问，乳腺癌的易感性与终身接触雌激素和孕激素(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)的使用方式类似于HRT，是广泛使用的激素方案的一个例子，可能会影响庞大人口中的乳腺癌化学预防。与HRT不同，OC在一生中被广泛使用，有时在青春期就开始使用，以控制生育和月经副作用。最近，随着连续给药方案的出现，激素撤除期被取消，女性可以选择接受数月或数年的连续激素暴露，而不会像通常伴随循环给药方案的那样，乳房或子宫重塑。基于OC消除月经和伴随的副作用的能力，在美国目前使用OC的成年女性中，有21%的人开始转向持续的养生法，这并不令人惊讶。因此，至关重要的是， 以确定持续暴露于OC是否具有增加乳腺癌的显著风险。尽管我们可能会预测风险增加(基于HRT的风险)，但骑自行车的女性经历了两种绝经期女性没有的组织反应：(I)激素反应导致上皮和间质血管(血管生成)增殖的周期，以及(Ii)细胞凋亡和腺体和间质血管退化的周期。这两个观察结果表明，持续服用OC有两种不同的潜在结果：(I)如果激素依赖的上皮和血管生成增殖对乳腺癌风险至关重要，我们预测持续使用OC将增加乳腺癌风险；(Ii)或者，如果激素停用导致腺体和间质血管退化和重塑导致乳腺癌风险增加(正如有人建议在哺乳期后退缩期间停用激素)，则连续服用OC可能会降低乳腺癌风险。这项提议旨在检验这两个交替的假说。目的1在自发性乳腺肿瘤发生的FVB-MMTV-HER-2/Neu模型中，比较周期(3天开始，1天停止)和持续剂量+/-OC改变自发肿瘤发生、进展和转移的能力。目的2利用TM2H可移植小鼠乳腺肿瘤细胞系，比较周期给药与连续给药+/-OC改变乳腺肿瘤生长的能力。将比较不同治疗组的乳腺肿瘤ER、PR和Her2/Neu表达的变化，血管以及增殖和凋亡指数。这些研究的主要结果是确定在两个不同的小鼠乳腺肿瘤模型中，持续剂量OC对原发和转移性乳腺肿瘤生长的影响，相对于没有OC或循环剂量OC。

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.