Membrane Progesterone Receptor Biology and Cancer Dynamics

Membrane progesterone receptors encompass two principal families: the Class II progestin and AdipoQ receptors (mPRα–ε, PAQR7–9) and the membrane-associated progesterone receptor components (PGRMC1/2 and related b5-like proteins). These receptors mediate rapid, non-genomic actions of progesterone distinct from nuclear receptor signalling. In cancer, membrane receptors influence kinase cascades, lipid metabolism and receptor tyrosine kinase interactions to regulate proliferation, survival, migration and angiogenesis. PGRMC1, for example, binds haem and partners with epidermal growth factor receptor and cytochromes P450, thereby promoting tumour growth and chemoresistance. mPRs activate G-protein-coupled pathways, modulate cAMP levels and engage lipid hydrolases, shaping membrane dynamics and downstream gene expression. Dysregulation of these receptors is implicated in diverse malignancies, underpinning prognostic biomarker discovery and novel therapeutic strategies that target receptor–ligand interactions, heme-mediated dimerisation or sphingolipid metabolism.

Research from Nature Portfolio

A seminal structural study revealed that PGRMC1 forms stable homodimers through stacking interactions of haem prosthetic groups. The five-coordinate haem iron engages tyrosine residues and mediates dimer assembly, which is essential for PGRMC1 to interact with epidermal growth factor receptor and cytochromes P450. Disruption of haem binding, either by carbon monoxide occupation of the axial site or by haem depletion, abrogates dimerisation, attenuates receptor tyrosine kinase signalling and restores chemosensitivity. This work uncovers a previously unrecognised mode of haem-dependent protein assembly in eukaryotes and highlights PGRMC1 dimerisation as a regulator of cancer proliferation and resistance to therapy.

Membrane Progesterone Receptor Biology and Cancer Dynamics publication trend

The graph below shows the total number of articles in membrane progesterone receptor biology and cancer dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Membrane progesterone receptor (mPR): A G-protein-coupled receptor family mediating rapid, non-genomic progesterone actions at the cell surface.

PGRMC1 (Progesterone receptor membrane component 1): A haem-binding protein that facilitates non-genomic steroid signalling and interacts with receptor tyrosine kinases and cytochromes P450.

Haem dimerisation: The stacking of haem prosthetic groups between protein subunits to stabilise receptor homodimers.

PAQR family: A group of membrane-associated receptors (PAQR5–9) that respond to progestins and regulate rapid steroid signalling.

Sphingolipid metabolism: A lipid pathway producing ceramides and sphingosine-1-phosphate, which influence cell survival and apoptosis.

ERK signalling pathway: A kinase cascade activated by membrane receptors that governs cell proliferation and gene expression.

References

1. Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance. Nature Communications (2016).
2. A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane. Cellular and Molecular Life Sciences (2024).
3. PAQR8 promotes breast cancer recurrence and confers resistance to multiple therapies. Breast Cancer Research (2023).
4. Progesterone Receptor Membrane Component 1 (PGRMC1) Modulates Tumour Progression, the Immune Microenvironment and the Response to Therapy in Glioblastoma. Cells (2023).
5. Pgrmc1 (Progesterone Receptor Membrane Component 1) Associates with Epidermal Growth Factor Receptor and Regulates Erlotinib Sensitivity*. Journal of Biological Chemistry (2010).
6. Membrane Associated Progesterone Receptors: Promiscuous Proteins with Pleiotropic Functions – Focus on Interactions with Cytochromes P450. Frontiers in Pharmacology (2017).