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.
Many women currently using oral contraceptives are opting to switch from a regimen of cyclic dosing (three weeks on, one week of hormone withdrawal) to continuous dosing (with no hormone withdrawal period). The goal of the current proposal is to evaluate whether these two methods of dosing differ in contributing to breast cancer risk, as a result of two different outcomes: (i) continuous dosing could cause longer periods of sustained hormonal stimulation, thus potentially increasing breast cancer risk, or (ii) continuous dosing, by eliminating the hormone withdrawal period, could decrease breast cancer risk through decreased mammary gland remodeling and by the loss of time during which progesterone sensitivity is re-set. These alternate outcomes will be evaluated using two complementary mouse models: (i) the spontaneous mammary tumor model of transgenic FVB-MMTV-Her2/neu mice, and (ii) a transplantation model using BALB/C mice receiving the syngeneic TM2H mouse mammary tumor cell line.
