Minireview: Progesterone Regulation of Proliferation in the Normal Human Breast and in Breast Cancer: A Tale of Two Scenarios?

Abstract

Progesterone (P), which signals through the P receptor (PR), is critical in normal development of the breast, but its signaling axis is also a major driver of breast cancer risk. Here we review recent advances in the understanding of P signaling in the normal human breast, with a focus on the importance of the balance between autocrine and paracrine signaling. To date, most data (which derive largely from mouse models or human breast cancer cell line studies) have demonstrated that the vast majority of PR+ cells appear to act as "sensor" cells, which respond to P stimulation by translating these hormonal cues into paracrine signals. However, growing evidence suggests that, dependent on the cellular context, P may also signal in an autocrine manner in a subset of cells in the normal mouse mammary gland and human breast. It has been suggested that it may be dysregulation of this autocrine signaling, resulting in a "switch" from a predominance of paracrine signaling to autocrine signaling in PR+ cells, which is an early event during breast tumorigenesis. This review summarizes current evidence in the literature that demonstrates the mechanisms through which P acts in the normal human breast, as well as highlighting the important questions that remain unanswered.

Figure 1.. Schematic diagrams of PRA and PRB structures depicting structural domains of each isoform.

DBD, DNA-binding domain; LBD, ligand-binding domain. Selected posttranslational modifications are also shown. P, phosphorylation; A, acetylation; SUMO, sumoylation.

Figure 2.. After P exposure, P enters a PR+ luminal cell (shown in blue) and binds to PR, which dimerises and transcribes target genes (eg, RANKL, WNT-4, NOTCH ligands, GH).

These signaling pathways then stimulate proliferation of neighboring PR− luminal cells (shown in red), potentially also involving cells in the basal cell layer (shown in purple). Not all of these pathways have been shown to be active in both the mouse (M) mammary gland as well as human (H) breast.

Figure 3.. A, During normal development, P stimulates proliferation of luminal cells by acting on PR+ luminal cells (shown in blue), which signal to neighboring PR− cells (shown in red) in a paracrine manner. In addition, P may further expand the epithelial compartment by direct stimulation of a subset of PR+ basal/progenitor cells (shown in light purple), which proliferate via autocrine mechanisms. B, When P levels are particularly high (during the luteal phase and pregnancy) or after exogenous hormone use, this proliferation may be increased, potentially providing a larger pool of PR+ progenitor cells susceptible to oncogenic hits, which may then increase the risk of tumorigenesis.