Alterations in progesterone receptor membrane component 2 (PGRMC2) in the endometrium of macaques afflicted with advanced endometriosis

Abstract

The hormonally driven expression and cell-specific localization patterns of the progesterone receptor membrane components (PGRMC1 and PGRMC2) in the macaque endometrium during the menstrual cycle are unknown. Additionally, the expression and localization patterns of PGRMC1 and PGRMC2 in the secretory eutopic endometrium of primates afflicted with endometriosis are also unknown. Therefore, we used real-time PCR to quantify transcript expression levels of the PGRMCs in well-defined samples of endometrium collected from artificially cycled macaques during the menstrual cycle, and in the secretory phase endometrium of naturally cycling macaques afflicted with endometriosis. In situ hybridization and immunocytochemistry were used to localize PGRMC1 and PGRMC2 mRNA and protein, respectively. We compared the patterns of expression and localization of the PGRMCs with the expression and localization patterns of nuclear progesterone receptor (PGR). PGRMC1 and PGR were elevated during the proliferative phases of the cycle, and then declined to nearly undetectable levels during the late secretory phase of the cycle. Levels of PGRMC2 were lowest during the proliferative phases of the cycle and then increased markedly during the secretory phases. Strong staining for PGRMC2 was localized to the luminal and glandular epithelia during the secretory phases. When compared with artificially cycled disease-free animals, macaques with endometriosis exhibited no changes in the expression or localization patterns for PGR and PGRMC1 but exhibited strikingly reduced levels of PGRMC2 transcript and altered intracellular staining patterns for the PGRMC2 protein. Collectively, these results suggest that membrane-bound PGRMC2 may provide a pathway of action that could potentially mediate the non-genomic effects of progesterone on the glandular epithelia during the secretory phase of the cycle. Further, reduced levels of membrane-bound PGRMC2 may be associated with the progesterone insensitivity often observed in the endometrium of primates afflicted with endometriosis.

Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors

“…PAQR8 expression is reduced in EV3 Ishikawa cells, which lack expression of the classical PRA and PRB receptors. Despite being shown previously to be regulated in the endometrium by steroid hormones [14] and fluctuating during phases of the estrous/menstrual cycles [14,17-20], basal PGRMC1 and PGRMC2 expression is not dependent upon the presence of PRA and PRB (Fig. 1C).…”

“…Given the abundant and endocrine regulated expression of PGRMC1 in the endometrium [10,14,17-20], the observation that PGRMC1 expression is elevated in various cancers such as ovarian and breast [21-26], and that P4 elicits actions in cells that lack expression of the classical PGR [9], the present study was undertaken to assess the role of PGRMC1 in endometrial cancer. Specifically, the objectives of this study were to: 1) evaluate PGRMC1 expression in endometrial cancer cell lines; 2) assess mitosis and cell death following treatment with P4 and/or chemotherapy in PGRMC1-intact and PGRMC1-deplete endometrial cancer cells; and 3) evaluate the onset of tumor formation and response to chemotherapy treatment in vivo following subcutaneous and intraperitoneal inoculation of PGRMC1-intact and PGRMC1-deplete endometrial cancer cells in immunocompromised mice.…”

Expression of Progesterone Receptor Membrane Component-2 Within the Immature Rat Ovary and Its Role in Regulating Mitosis and Apoptosis of Spontaneously Immortalized Granulosa Cells1

“…PGRMC2 is the second member of the membraneassociated PGR family to be identified and to date has been shown to be expressed in several different cells and tissues, including mouse [28], primate [29], and bovine uterine endometrial cells [30] and oviductal epithelial cells [31] as well as placenta [32] and human granulosa/luteal cells obtained from patients undergoing in vitro fertilization [21]. In addition, PGRMC2 is expressed in peripheral blood mononuclear cells [33], neonatal rat ovaries [20], and both ovarian [24] and breast cancers [34].…”

Identification of a novel putative interaction partner of the nucleoporin ALADIN

“…These receptors, restricted to the endoplasmic reticulum (ER), are thought to act on mitosis while localising to the somatic spindle apparatus and to regulate the activity of some CYP P450 enzymes (e.g. CYP21A2) (Keator et al, 2012; Peluso et al, 2014; Wendler and Wehling, 2013). …”