Progesterone and Overlooked Endocrine Pathways in Breast Cancer Pathogenesis

Abstract

Worldwide, breast cancer incidence has been increasing for decades. Exposure to reproductive hormones, as occurs with recurrent menstrual cycles, affects breast cancer risk, and can promote disease progression. Exogenous hormones and endocrine disruptors have also been implicated in increasing breast cancer incidence. Numerous in vitro studies with hormone-receptor-positive cell lines have provided insights into the complexities of hormone receptor signaling at the molecular level; in vivo additional layers of complexity add on to this. The combined use of mouse genetics and tissue recombination techniques has made it possible to disentangle hormone action in vivo and revealed that estrogens, progesterone, and prolactin orchestrate distinct developmental stages of mammary gland development. The 2 ovarian steroids that fluctuate during menstrual cycles act on a subset of mammary epithelial cells, the hormone-receptor-positive sensor cells, which translate and amplify the incoming systemic signals into local, paracrine stimuli. Progesterone has emerged as a major regulator of cell proliferation and stem cell activation in the adult mammary gland. Two progesterone receptor targets, receptor activator of NfκB ligand and Wnt4, serve as downstream paracrine mediators of progesterone receptor-induced cell proliferation and stem cell activation, respectively. Some of the findings in the mouse have been validated in human ex vivo models and by next-generation whole-transcriptome sequencing on healthy donors staged for their menstrual cycles. The implications of these insights into the basic control mechanisms of mammary gland development for breast carcinogenesis and the possible role of endocrine disruptors, in particular bisphenol A in this context, will be discussed below.

Figure 1.

Mammary gland development in the mouse. Schematic representation of distinct stages of postnatal mammary gland development. In the pubertal mammary gland, terminal end buds appear at the tips of the ducts triggered by ovarian estrogens, which require epithelial ER. The ducts elongate and bifurcate until the edges of the fat pad are reached, which coincides with sexual maturity. Repeated stimulation with progesterone, as occurs during estrous cycles, results in the formation of side branches, which bud from preexisting ducts at a 90° angle. Side branch formation is blocked in PR^−/− mammary epithelia. Ductal complexity continues to increase during the first half of pregnancy. In the last third of pregnancy, secretory structures of saccular shape, alveoli, sprout all over the ductal system and differentiate into milk-producing units under the control of prolactin receptor signaling.

Figure 2.

The human menstrual cycle. Graph showing serum levels of the major fluctuating hormones across a menstrual cycle. Note that progesterone levels peak during luteal phase. Estrogen reaches its maximum levels during follicular phase; a smaller peak follows during luteal phase. Cell proliferation is observed in the breast epithelium in the luteal phase and positively correlated with serum progesterone levels.

Figure 3.

Signaling downstream of progesterone. Schematic representation of the bilayered mammary epithelium and the intra- and intercellular signaling activated by progesterone. An inner, luminal layer is surrounded by myoepithelial/basal cells, which are in contact with the basal lamina. Progesterone binds its receptor in a subset of HR+ luminal cells, the sensor cells (light blue). In certain PR+ cells, it induces cell proliferation by a Cyclin D1-dependent mechanism (cell-intrinsic signaling). It induces RANKL, which elicits cell proliferation in neighboring HR− cells (paracrine homotypic) and wnt4, which acts on myoepithelial cells (paracrine heterotypic) and increases stem cell activity.

Figure 4.

Model of how endocrine factors affect breast cancer risk. Graph showing breast cancer risk plotted over a woman's age, depending on whether or not she was exposed to DES or BPA. With each menstrual cycle, breast cancer risk increases through progesterone-induced events during luteal phase. The model proposes that perinatal exposure to endocrine disruptors increases the sensitivity of the breast to progesterone and hence increases the slope of the curve (top panel and inset). Various factors such as RANKL, WNT4, epiregulin, CyclinD1, ID4, and calcitonin, which act through distinct mechanisms and have been shown to have distinct biologically functions, have been implicated in the biological response to progesterone that may be amplified due to perinatal exposure.