New insights into the functions of progesterone receptor (PR) isoforms and progesterone signaling

Abstract

Progesterone, the ovarian steroid hormone, regulates a plentitude of biological processes in tissues ranging from the brain to bones. Recognizing the role of progesterone and its receptors in physiological processes and maladies can prevent and treat various diseases. Apart from its physiological functions, its role in developing diseases, especially breast cancer, is a recent topic of deliberation. There exists conflicting experimental and epidemiological evidence linking progesterone to breast cancer. This review tries to describe the physiological functions of progesterone and its receptors, genomic and non-genomic signaling, splice variants, and a different aspect of progesterone signaling. Furthermore, we seek to address or attempt to discuss the following pertinent questions on steroid hormone signaling; How does progesterone influence breast cancer progression? How does it change the molecular pathways in breast cancer with different receptor statuses, the specific role of each isoform, and how does the ER/and PR ratio affect progesterone signaling?

Keywords: Progesterone; cancer; physiological functions; progesterone receptor.

Figure 1

Structure of different isoforms of progesterone receptors. The PR consist of four different domains, NTD represents the N-terminal transactivation domain, DBD represents the DNA binding domain, a hinge region, and LBD represent the Ligand-binding domain. AF1, AF2, and AF3 are activation function domains.

Figure 2

Structure of PGRMC1. PGRMC1 consist of an N terminal TM domain, a cytochrome b5 domain, SH2, and SH3 binding domains, and sites for kinase binding (indicated by asterisks).

Figure 3

Anti-inflammatory and immunomodulatory actions of progesterone. Progesterone inhibits synthesis of pro-inflammatory cytokines by macrophages and dendritic cells. Progesterone also helps to produce anti-inflammatory cytokines by CD4+ T-helper cells and switch to Th2 type anti-inflammatory response. Moreover, both estradiol and progesterone stimulate the expansion of T-regulatory cells, thus supporting immune tolerance.

Figure 4

Venn-Euler diagram of commonly expressed proteins in different breast cancer cell lines. Breast cancer cell lines MCF-7, MDAMB-231, and SKBR3 were treated with progesterone for 48 hr. Protein samples were collected by cell lysis and further analyzed by LC-MS-MS analysis and total proteins are represented as Venn-Euler diagram.