The Role of Progesterone in the Etiology of Breast Cancer

While E's role in the etiology of BC has been extensively studied, and E has been shown to play multiple roles in BC pathways, less is known about the relationship between P and BC etiology. Initially, P was thought to protect the breast from cancer based on its anti-proliferative effects on the endometrium. However, several recent studies suggest that P is involved in multiple pathways associated with BC. In 1994, Shi, et al. (39) summarized evidence documenting the role of P in the initiation and promotion of BC, including how P: 1. Stimulates growth in the normal human breast (in contrast to its effect on the endometrium). 2. Has mitogenic effects on BC cell lines. 3. Promotes mammary tumor growth in rodents. 4. Induces mitogenic growth factors and their receptors in hormone receptor positive BC cells. 5. Regulates receptors for adhesion molecules involved in metastases. 6. Tumorigenesis is inhibited by anti-progestins. Details regarding this evidence and more recent work documenting links between P and breast/mammary gland carcinogenesis are discussed below.

P's central role in the proliferation and development of the normal breast are well documented (40). In 1977, two studies evaluating cyclic variations in DNA synthesis in breast epithelium during the menstrual cycle were published (41,42). These studies established that DNA synthesis is low during the follicular phase (E dominant) and high during the luteal phase (P dominant). Subsequent studies identified that this fluctuation in DNA synthesis specifically takes place in breast lobular epithelium, both during natural menstrual cycles (43) and in cycles regulated by oral contraceptive use (44). These studies also demonstrated that after lobular proliferation tapers off at the end of the luteal phase, a period of apoptotic activity occurs. It was hypothesized that because the increase in DNA synthesis occurs during the luteal phase, P, rather than E (long believed to be the primary promoter of breast proliferation), was primarily responsible for stimulating lobular epithelial cell proliferation in the breast. Experimental data ultimately substantiated this hypothesis (45), and now there is general agreement that DNA synthesis increases in the luteal phase of the natural menstrual cycle due to the peaking of P levels.

Developmentally, P is involved in the formation of lobular-alveolar structures that occurs during pregnancy. A study comparing normal mice to mice that lack the PR found that while the PR-null mice developed normal ductal structures, they did not form any lobular-alveolar structures when exposed to E and P (46). P's proliferative effects appear to be mediated through its regulation of genes associated with cell cycle progression, growth factors, and growth factor receptors. Treatment of cells arrested in G1 with progestin stimulates them to progress through the cell cycle and induces cyclins (including cyclin D1), cyclin-dependent kinases, and c-myc and c-fos (protooncogenes involved in cell proliferation) (47, 48). Further, the increases in cyclin D1 and c-myc can be blocked by administering the anti-progestin RU 38486, indicating the key role of P's interactions with the PR in stimulating cell cycle progression. P induces growth factors that stimulate proliferation, such as epidermal growth factor (EGF) (49-51) and tumor growth factor (TGF)-a, and suppresses growth factors that inhibit proliferation, such as Thus, there are multiple lines of evidence suggesting that P has proliferative effects on the normal breast. However, the mechanisms underlying these effects remain to be elucidated, and additional research in this area is required.

Though P's involvement in the proliferation and development of the normal human breast is well established, its effects on BC cells remain controversial because depending on the model, cell type, and duration oftreatment, P can act as an inducer or represser of BC cell proliferation. A detailed discussion of this literature is beyond the scope of this review, but it has been hypothesized by Lange, et al. that these apparent contradictory effects can be explained if P acts as a priming factor that mediates cross-talk between proliferative and anti-proliferative signals (53). Thus, the timing, dose, and route of P administration can alter the balance between these signals in different directions. However, these mechanisms and our perception of how P is related to human BC is not well-understood.

Our understanding ofP's mechanism of action was further complicated by the identification of two distinct isoforms of the PR-A and PR-B (54). Both are transcribed from a single gene, but differ in that PR-A lacks the 164 N-terminal structure present in PR-B. Although both PRs have the same affinity for P, these two isoforms have different functions with respect to breast development and gene regulation. Studies using a transgenic mouse model carrying additional PR-A develop mammary glands with excessive lateral ductal branching, but lack lobular-alveolar development (55). Alternatively, mice with additional PR-B exhibit an excessive amount of lobular-alveolar growth, but exhibit an arrested development of branching ductal structures (56). With respect to transcriptional activity, PR-A does not activate transcription but is a strong represser of PR-B, while PR-B is a transcriptional activator (57). Since PR-B is critical for lobular development and stimulates the transcription of genes implicated in BC, one potential mechanism by which the use of exogenous P could promote lobular, but not ductal, carcinoma is by its PR-B mediated effects. However, further research is required to test this hypothesis since no studies have been reported comparing the expression of PR's isoforms in IDC vs ILC. A study evaluating only IDC tumors reported that 66% expressed PR-A and 55% PR-B (58).

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