Progesterone and Breast Cancer

Abstract

Synthetic progestogens (progestins) have been linked to increased breast cancer risk; however, the role of endogenous progesterone in breast physiology and carcinogenesis is less clearly defined. Mechanistic studies using cell culture, tissue culture, and preclinical models implicate progesterone in breast carcinogenesis. In contrast, limited epidemiologic data generally do not show an association of circulating progesterone levels with risk, and it is unclear whether this reflects methodologic limitations or a truly null relationship. Challenges related to defining the role of progesterone in breast physiology and neoplasia include: complex interactions with estrogens and other hormones (eg, androgens, prolactin, etc.), accounting for timing of blood collections for hormone measurements among cycling women, and limitations of assays to measure progesterone metabolites in blood and progesterone receptor isotypes (PRs) in tissues. Separating the individual effects of estrogens and progesterone is further complicated by the partial dependence of PR transcription on estrogen receptor (ER)α-mediated transcriptional events; indeed, interpreting the integrated interaction of the hormones may be more essential than isolating independent effects. Further, many of the actions of both estrogens and progesterone, particularly in "normal" breast tissues, are driven by paracrine mechanisms in which ligand binding to receptor-positive cells evokes secretion of factors that influence cell division of neighboring receptor-negative cells. Accordingly, blood and tissue levels may differ, and the latter are challenging to measure. Given conflicting data related to the potential role of progesterone in breast cancer etiology and interest in blocking progesterone action to prevent or treat breast cancer, we provide a review of the evidence that links progesterone to breast cancer risk and suggest future directions for filling current gaps in our knowledge.

Graphical Abstract

Figure 1.

Progesterone levels across the lifespan: [Inset A) across the menstrual cycle, B) across pregnancy]. Legend: Progesterone levels increase from <1 ng/mL before age 10 to 10–12 ng/mL around puberty. Throughout the reproductive years levels range from 3 to 35 ng/mL in the luteal phase, decreasing in the late luteal phase, and are <1 ng/mL in the follicular phase (Inset A). In postmenopausal women, progesterone levels wane to <0.2 ng/mL. In pregnant women (Inset B), progesterone levels increase from 10–35 ng/mL in the 1^st trimester to 100–300 ng/mL in the 3^rd trimester; progesterone levels then drop to low levels postnatally as prolactin levels increase to facilitate lactation and return to average reproductive age ranges when ovulation returns.

Figure 2.

Chemical structures of progesterone and testosterone and for comparison common C-21 and C-19 related progestins.

Figure 3.

Progesterone regulation of functionally-defined mammary epithelial cell hierarchy.

Figure 4.

Primary pathways of progesterone metabolism in breast tissue. Legend: In normal tissue, pregnenes (progesterone is a pregnene) are the predominant compounds. All of the 4 pregnenes (not shown) can be irreversibly converted to 5α-pregnane (respectively) via 5α-reductase. The 2 metabolites, 3αHP and 5αP, show the greatest differences between tumorous and nontumorous tissue; the ratio of 5αP-to-3αHP is more than 10-fold higher comparing breast tumors to normal breast tissue. Metabolic activities of the hormones are similar in pre- and postmenopausal women, by age, and by ER-status.