Effects of Continuous versus Cyclic Oral Contraceptives on Mammary Tumor Growth

描述（由申请人提供）：毫无疑问，乳腺癌易感性与终身暴露于雌激素和孕激素（E+P）密切相关。使用广泛使用的激素替代疗法（HRT）延长E+P暴露可增加绝经后妇女患乳腺癌的风险。口服避孕药（OC）的使用，以类似于HRT的方式，是广泛使用的激素方案的一个例子，有可能影响巨大人群中的乳腺癌化学预防。与HRT不同，OC在一生中使用很长时间，有时早在青春期就开始使用，以控制生育和月经副作用。随着最近连续给药方案的出现，其中激素停药期被消除，女性可以选择经历数月或数年的连续激素暴露，而不会重塑通常伴随周期给药方案的乳房或子宫。基于OC消除月经和伴随的副作用的能力，美国目前使用OC的约21%的成年女性中的许多人已经开始转向连续方案，这并不奇怪。因此， 以确定持续暴露于OC是否具有增加乳腺癌的显著风险。虽然我们可能预测风险增加（基于HRT的风险），但骑自行车的女性会经历两种类型的组织反应，而这在绝经期女性中不会发生：（i）响应激素的上皮和基质血管（血管生成）增殖周期，以及（ii）细胞凋亡和腺体和基质血管退化周期。这两个观察结果表明，连续OC给药的两个替代的潜在结果：（i）如果乳腺癌依赖性上皮和血管生成增殖是乳腺癌风险的关键，我们预测连续OC使用将增加乳腺癌风险;（ii）另一方面，如果腺体和间质血管退化和重塑对激素戒断的反应有助于乳腺癌的风险，（如已提出的哺乳期后退化期间激素戒断），那么连续给药可能会降低乳腺癌的风险。本提案旨在检验这两个备选假设。目的1将比较周期性（给药3天，停药1天）与连续给药+/- OC改变自发性乳腺肿瘤发生的FVB-MMTV-Her-2/Neu模型中自发性肿瘤发生、进展和转移的能力。目的2将使用TM 2 H可移植小鼠乳腺肿瘤细胞系比较循环与连续给药+/- OC改变乳腺肿瘤生长的能力。将比较来自不同治疗组的乳腺肿瘤的ER、PR和Her 2/Neu表达、血管分布以及增殖和凋亡指数的变化。这些研究的主要结果是确定OC连续给药相对于无OC或OC循环给药对两种不同小鼠乳腺肿瘤模型中原发性和转移性乳腺肿瘤生长的影响。

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.