The Role of Membrane Progesterone Receptor Associated Proteins in Gynecological and Reproductive Disorders, and Cancers: An Editor’s Historical Perspective
Part 3: The Role of mPRs and Immunomodulatory Proteins in Development of Benign and Malignant Tumors and Endometriosis
The Probable Role of PIBF in Allowing Cancer Progression and the Potential for a Novel Highly Effective Treatment
Jerome H Check* and Naomi Ganpo-Nkwenkwa
ABSTRACT
This is the third and final perspective discussing the critical role of membrane progesterone receptors (MPRs) in allowing the achievement of a live delivery, but also its role in allowing malignant tumors to develop and metastasize by negating immune surveillance, and the possible role they play in the development of endometriosis and even uterine leiomyomata. Part 1 discussed the molecular biology of MPRs and their function in allowing both the fetus and malignant tumor to proliferate, invade normal tissue, and evade immune surveillance. Part 2 discussed the role of mPRs in establishing a pregnancy and preventing both miscarriage and preterm labor. This final perspective provides the historical studies involving evidence that drugs that negate the function of mPRs cannot only inhibit cancer cell lines from proliferating, but also demonstrate marked clinical benefit, not only for several types of spontaneous murine cancers, but also very terminal human patients with a large variety of cancers by treating these moribund patients with a selective progesterone receptor modulator (SPRM) especially mifepristone. The hypothetical mechanism of action of SPRMs is by inhibiting the production of immunomodulatory proteins e.g., the progesterone induced blocking factor (PIBF) or the progesterone receptor membrane component-1 (PGRMC-1) proteins that occur when the mPR is activated by progesterone (as in pregnancy) or other ligands made by cancer cells. Whereas splice variance of the 90kDa parent protein of PIBF seem to function to inactivate the killing aspects of natural killer (NK) cells, macrophages, and cytotoxic T cells, the parent 90kDa protein may be involved in rapid proliferation of cells and invasion into normal tissue for both the fetus and the malignant tumor. This perspective hypothesizes how this 90kDa parent PIBF protein may also allow endometriosis or even uterine leiomyomata to grow and invade normal tissue and even how it may help eradicate implants to spread to ectopic places. This could possibly explain the paradox of the use of progestins to ameliorate the symptoms of endometriosis or estrogen suppressing drugs, yet also respond to SPRMs which theoretically should increase estrogen simulation of endometrial implants. However, by blocking mPRs and thus inhibiting production of immunomodulatory proteins, e.g., PIBF, SPRMs could improve endometriosis by inhibiting the effect of PIBF on proliferation and invasion of normal tissue.
