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Crosstalk between progesterone receptor membrane component 1 and estrogen receptor α promotes breast cancer cell proliferation

Abstract

Progesterone (P4) and estradiol (E2) have been shown to stimulate and regulate breast cancer proliferation via classical nuclear receptor signaling through progesterone receptor (PR) and estrogen receptor α (ERα), respectively. However, the basis of communication between PR/ERα and membrane receptors remains largely unknown. Here, we aim to identify classical and nonclassical endocrine signaling mechanisms that can alter cell proliferation through a possible crosstalk between PR, ERα, and progesterone receptor membrane component 1 (PGRMC1), a membrane receptor frequently observed in breast cancer cells. While P4 and E2 treatment increased cell proliferation of ER+/PR+/PGRMC1 overexpressing breast cancer cells, silencing ERα and PR or treatment with selective estrogen receptor modulator (SERM) tamoxifen, or (PR-antagonist) RU-486 decreased cell proliferation. All four treatments rapidly altered PGRMC1 mRNA levels and protein expression. Furthermore, P4 and E2 treatments rapidly activated EGFR a known interacting partner of PGRMC1 and its downstream signaling. Interestingly, downregulation of ERα by tamoxifen and ERα silencing decreased the expression levels of PGRMC1 with no repercussions to PR expression. Strikingly PGRMC1 silencing decreased ERα expression irrespective of PR. METABRIC and TCGA datasets further demonstrated that PGRMC1 expression was comparable to that of ERα in Luminal A and B breast cancers. Targeting of PR, ERα, and PGRMC1 confirmed that a crosstalk between classical and nonclassical signaling mechanisms exists in ER+ breast cancer cells that could enhance the growth of ER+/PR+/PGRMC1 overexpressing tumors.

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Fig. 1: P4, RU-486, E2, and tamoxifen alter PGRMC1 mRNA expression.
Fig. 2: PGRMC1 protein expression is quickly altered by P4, RU-486, E2, and tamoxifen.
Fig. 3: Survival pathways associated with PGRMC1 are activated by P4 and E2.
Fig. 4: PGRMC1 and ERα regulate each other irrespective of PR.
Fig. 5: METABRIC and TCGA dataset analysis of ESR1, PGR, and PGRMC1 in breast cancer patients.
Fig. 6: PGRMC1 expression in human breast cancers and crosstalk model between PGRMC1/ERα.

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Acknowledgements

We thank the Texas Tech University Health Sciences Center El Paso for supporting this project.

Funding

Breast Cancer Discretionary Fund from Texas Tech University Health Sciences Center El Paso.

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Correspondence to Rajkumar Lakshmanaswamy.

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Pedroza, D.A., Subramani, R., Tiula, K. et al. Crosstalk between progesterone receptor membrane component 1 and estrogen receptor α promotes breast cancer cell proliferation. Lab Invest (2021). https://doi.org/10.1038/s41374-021-00594-6

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