Pleiotropic Actions of PGRMC Proteins in Cancer

Abstract

Progesterone receptor membrane component (PGRMC) proteins play important roles in tumor growth, progression, and chemoresistance, of which PGRMC1 is the best characterized. The ancestral member predates the evolution of metazoans, so it is perhaps not surprising that many of the purported actions of PGRMC proteins are rooted in fundamental metabolic processes such as proliferation, apoptosis, and DNA damage responses. Despite mediating some of the actions of progesterone (P4) and being fundamentally required for female fertility, PGRMC1 and PGRMC2 are broadly expressed in most tissues. As such, these proteins likely have both progesterone-dependent and progesterone-independent functions. It has been proposed that PGRMC1 acquired the ability to mediate P4 actions over evolutionary time through acquisition of its cytochrome b5-like heme/sterol-binding domain. Diverse reproductive and nonreproductive diseases associate with altered PGRMC1 expression, epigenetic regulation, or gene silencing mechanisms, some of which include polycystic ovarian disease, premature ovarian insufficiency, endometriosis, Alzheimer disease, and cancer. Although many studies have been completed using transformed cell lines in culture or in xenograft tumor approaches, recently developed transgenic model organisms are offering new insights in the physiological actions of PGRMC proteins, as well as pathophysiological and oncogenic consequences when PGRMC expression is altered. The purpose of this mini-review is to provide an overview of PGRMC proteins in cancer and to offer discussion of where this field must go to solidify PGRMC proteins as central contributors to the oncogenic process.

Keywords: PGRMC1; PGRMC2; breast; cancer; endometrium; progesterone.

Figure 1.

(A) Expression of PGRMC1 and PGRMC2 in patient-derived xenograft (PDX (57)) endometrial cancer cells counterstained with 4′,6-diamidino-2-phenylindole (DAPI; n = 3). (B) Western blot showing expression of PGRMC1 in PDX endometrial cancer cells as a 25 kilodalton (K) monomer, 50 K dimer, and 75 K oligomer.

Figure 2.

Metascape (131) was used to generate a gene ontology profile from HA-tagged PGRMC1-interacting proteins isolated from PaCa2 cancer cells (131). Proteins were clustered based on enrichment terms and plotted against a P value in log base 10, which served as the multitest adjusted P value. Note the presence of several clusters associated with mRNA processing and transcriptional or translational regulation.