Estrogen is the major mitogenic stimulus of mammary gland development during puberty wherein ER signaling acts to induce abundant PR expression. PR signaling, in contrast, is the primary driver of mammary epithelial cell proliferation in adulthood. The high circulating levels of
progesterone during pregnancy signal through PR, inducing expression of the
prolactin receptor (PRLR). Cooperation between PR and
prolactin (PRL) signaling, via regulation of downstream components in the PRL signaling pathway including JAKs and STATs, facilitates the alveolar morphogenesis observed during pregnancy. Indeed, these pathways are fully integrated via activation of shared signaling pathways (i.e. JAKs, MAPKs) as well as by the convergence of PRs and STATs at target genes relevant to both mammary gland biology and
breast cancer progression (i.e. proliferation, stem cell outgrowth, tissue cell type heterogeneity). Thus, rather than a single mediator such as ER,
transcription factor cascades (ER>PR>STATs) are responsible for rapid proliferative and developmental programming in the normal mammary gland. It is not surprising that these same mediators typify uncontrolled proliferation in a majority of breast
cancers, where ER and PR are most often co-expressed and may cooperate to drive malignant
tumor progression. This review will primarily focus on the integration of PR and PRL signaling in
breast cancer models and the importance of this cross-talk in
cancer progression in the context of mammographic density. Components of these PR/PRL signaling pathways could offer alternative
drug targets and logical complements to anti-ER or anti-
estrogen-based endocrine
therapies.