Cellular and Molecular Biology

Progesterone receptor membrane component 1 promotes the growth of breast cancers by altering the phosphoproteome and augmenting EGFR/PI3K/AKT signalling

Subjects

Abstract

Background

Increased expression of the progesterone receptor membrane component 1 (PGRMC1) has been linked to multiple cancers, including breast cancer. Despite being a regulatory receptor and a potential therapeutic target, the oncogenic potential of PGRMC1 has not been studied.

Methods

The impact of PGRMC1 on breast cancer growth and progression was studied following chemical inhibition and alteration of PGRMC1 expression, and evaluated by using online-based gene expression datasets of human breast cancer tissue. MTS, flow cytometry, qPCR, Western blotting, confocal microscopy and phosphoproteome analysis were performed.

Results

We observed higher PGRMC1 levels in both ER-positive ZR-75-1 and TNBC MDA-MB-468 cells. Both chemical inhibition and silencing decreased cell proliferation, induced cell-cycle arrest, promoted apoptosis and reduced the migratory and invasive capabilities of ZR-75-1 and MDA-MB-468 cells. Further, phosphoproteome analysis demonstrated an overall decrease in activation of proteins involved in PI3K/AKT/mTOR and EGFR signalling pathways. In contrast, overexpression of PGRMC1 in non-malignant MCF10A cells resulted in increased cell proliferation, and enhanced activity of PI3K/AKT/mTOR and EGFR signalling pathways.

Conclusions

Our data demonstrate that PGRMC1 plays a prominent role in regulating the growth of cancer cells by altering the PI3K/AKT/mTOR and EGFR signalling mechanisms in both ER-positive and TNBC cells.

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Fig. 1: PGRMC1 is highly expressed in ER-positive and TNBCs.
Fig. 2: AG-205 selectively inhibits ER-positive and TNBC cell growth and survival.
Fig. 3: Silencing PGRMC1 inhibits growth and survival of breast cancer cells.
Fig. 4: Phosphoproteome analysis connects PGRMC1 signalling to breast cancer survival pathways.
Fig. 5: Inhibition of PGRMC1 disrupts AKT/mTOR and EGFR phosphorylation sites.
Fig. 6: PGRMC1 overexpression alters the phosphoproteome and promotes cell survival of normal breast cells.

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Acknowledgements

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

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Authors

Contributions

Conception and design: R.L.; development of methodology: D.A.P., R.S. and VR; acquisition of data: D.A.P. and V.R.; analysis and interpretation of data: R.L., D.A.P., V.R., A.B.B. and A.G.; writing, review and/or revision of the paper: D.A.P., V.R. and R.L.; study supervision: R.L. and R.S. All authors read and approved the final paper.

Corresponding author

Correspondence to Rajkumar Lakshmanaswamy.

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MCF12A, MCF10A, MCF7, T47D, ZR-75-1, MDA-MB-231 and MDA-MB-468 cell lines were acquired from the American Type Culture Collection (Manassas, VA, USA).

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Not applicable.

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All data generated or analysed during this study are included in this published article [and its Supplementary information files].

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The authors declare no competing interests.

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

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Pedroza, D.A., Rajamanickam, V., Subramani, R. et al. Progesterone receptor membrane component 1 promotes the growth of breast cancers by altering the phosphoproteome and augmenting EGFR/PI3K/AKT signalling. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-0992-6

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