Researchers have identified unique isoform-specific functions of phosphorylated progesterone receptors (PRs) as pathway drivers in the development of luminal breast cancer, according to a study recently published in Endocrinology.
Researchers led by Carol A. Lange, PhD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis, point out that luminal, or estrogen receptor (ER)-positive breast cancer accounts for about 75% of all breast cancer cases, and that total PR expression, rather than isoform-specific PR expression, is measured in breast tumors as an indicator of functional ER. “PR has been emerging as a context-dependent driver of luminal breast cancer phenotypes associated with tumor progression in vitro and in vivo,” the authors write. “However, progress in the development of highly selective anti-progestins for clinical use as PR-targeted therapies has been limited.”
Lange and her team write that in breast tissue, PR signaling is mediated by two co-expressed PR isoforms, full-length PR-B and N-terminal truncated PR-A (truncated of the first 164 amino acids found in PR-B, termed the B-upstream segment). These isoforms regulate overlapping, but distinct, gene sets. For example, animal studies have shown that PR-B is required for normal mammary gland development, while PR-A is essential for uterine development and fertility. The researchers wanted to better understand how these isoforms regulate breast cancer stem cells (CSCs) or stem-like cells in luminal breast cancer models.
The researchers found that PR-A can limit proliferation, but is a dominant driver of CSC expansion in T47D models, while PR-B is a potent driver of anchorage-independent proliferation. “Relative to what is known about ER signaling, PR isoforms have been grossly understudied in luminal breast cancer biology,” the authors write. “Our data have revealed opposing functions for the PR isoforms in proliferation vs breast CSC biology and identified phosphorylated Ser294 PR-A as a potent driver of breast CSC expansion.” They go on to speculate that given the recent finding that luminal A-type breast cancers are PR-A rich, their findings could explain why women diagnosed with luminal-A breast cancer have an initial good response to endocrine therapies but remain at risk for late recurrence.
Lange and her team conclude that phospho-PR isoforms could serve as clinical biomarkers to identify patients with breast cancer at risk of metastasis. “A deeper understanding of PR isoform-specific actions, including PR-phosphorylated species and their target gene cofactors, might provide information on the mechanisms of late recurrence in luminal breast cancer and reveal new approaches to pharmacologically target phosphorylated PR isoforms as potent drivers of breast CSC biology,” the authors write.