The role of progesterone and the progesterone receptor in cancer: progress in the last 5 years

ABSTRACT

Introduction

Patients with various advanced cancers devoid of nuclear progesterone receptors (nPR) have demonstrated increased quality and length of life when treated with the PR modulator mifepristone, which likely works by interacting with membrane PRs (mPR).

Areas covered

Two immunomodulatory proteins are discussed that seem to play a role in cancers that proliferate whether the malignant tumor is positive or negative for the nPR. These two proteins are the progesterone receptor membrane component-1 (PGRMC-1) and the progesterone-induced blocking factor (PIBF). Both PGRMC-1 and the parent form of PIBF foster increased tumor aggressiveness, whereas splice variants of the 90 kDa form of PIBF inhibit immune response against cancer cells.

Expert opinion

The marked clinical improvement following 200–300 mg of mifepristone is likely related to blocking PIBF. In the low dosage used, mifepristone likely acts as an agonist for PGRMC-1 protein. Mifepristone may be less effective for cancers positive for the nPR because the nPR may be protective and blocking it may have detrimental effects. Based on this hypothetical model, the development of other potential treatment options to provide even greater efficacy for treating cancer are discussed.

KEYWORDS:

• Advanced cancers
• membrane progesterone receptor
• nuclear progesterone receptor
• palliation
• progesterone-induced blocking factor
• progesterone receptor membrane component-1
• progesterone receptor modulator

Article highlights

• Activation of the nuclear progesterone receptor in certain cancers may help the host to inhibit tumor virulence.

• Activation of fast acting membrane progesterone receptors (mPRs) enable the malignant tumor to become more aggressive.

• Activation of mPRs leads to the production of molecules that also help the fetus to proliferate and avoid immune surveillance.

• One of the products of mPR activation is the progesterone induced blocking factor (PIBF).

• Whereas the 90 kDa parent form of PIBF may aid in cell regulation and thus may arrest the growth of the cancer cells (and fetus), splice variants of shorter molecular weight may help to inhibit cellular immune reactions against the cancer cells.

• Another product of mPR activation is the progesterone receptor membrane component (PGRMC-1) protein, which increases tumor proliferation and invasion and possibly metastasis.

• Probably, by inhibiting PIBF with the progesterone receptor modulator mifepristone, acting as an antagonist, end-stage cancers are inhibited from further metastasis. It also helps stabilize existing lesions, providing significant improvement in longevity and quality of life in patients with advanced cancers with no other options.

Declaration of interest

Corcept Inc. has provided the 300 mg dosage of mifepristone free to patients enrolled in the aforementioned investigator-initiated non-small cell lung cancer study but provided no other funding. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.