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




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.


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.


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.


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. & Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).

    Google Scholar 

  2. 2.

    Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 69, 7–34 (2019).

    Google Scholar 

  3. 3.

    Spring, L. M., Gupta, A., Reynolds, K. L., Gadd, M. A., Ellisen, L. W., Isakoff, S. J. et al. Neoadjuvant endocrine therapy for estrogen receptor-positive breast cancer: a systematic review and meta-analysis. JAMA Oncol. 2, 1477–1486 (2016).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Burstein, H. J., Prestrud, A. A., Seidenfeld, J., Anderson, H., Buchholz, T. A., Davidson, N. E. et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J. Clin. Oncol. 28, 3784–3796 (2010).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Slamon, D., Eiermann, W., Robert, N., Pienkowski, T., Martin, M., Press, M. et al. Adjuvant trastuzumab in HER2-positive breast cancer. N. Engl. J. Med. 365, 1273–1283 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Bianchini, G., Balko, J. M., Mayer, I. A., Sanders, M. E. & Gianni, L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat. Rev. Clin. Oncol. 13, 674–690 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Chang, M. Tamoxifen resistance in breast cancer. Biomol. Ther. (Seoul.) 20, 256–267 (2012).

    CAS  Google Scholar 

  8. 8.

    Rexer, B. N. & Arteaga, C. L. Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit. Rev. Oncog. 17, 1–16 (2012).

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Wein, L. & Loi, S. Mechanisms of resistance of chemotherapy in early-stage triple negative breast cancer (TNBC). Breast 34, S27–S30 (2017).

    PubMed  Google Scholar 

  10. 10.

    Kabe, Y., Nakane, T., Koike, I., Yamamoto, T., Sugiura, Y., Harada, E. et al. Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance. Nat. Commun. 7, 11030 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Hughes, A. L., Powell, D. W., Bard, M., Eckstein, J., Barbuch, R., Link, A. J. et al. Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes. Cell Metab. 5, 143–149 (2007).

    CAS  PubMed  Google Scholar 

  12. 12.

    Peluso, J. J., Liu, X., Saunders, M. M., Claffey, K. P. & Phoenix, K. Regulation of ovarian cancer cell viability and sensitivity to cisplatin by progesterone receptor membrane component-1. J. Clin. Endocrinol. Metab. 93, 1592–1599 (2008).

    CAS  PubMed  Google Scholar 

  13. 13.

    Mir, S. U., Ahmed, I. S., Arnold, S. & Craven, R. J. Elevated progesterone receptor membrane component 1/sigma-2 receptor levels in lung tumors and plasma from lung cancer patients. Int J. Cancer 131, E1–E9 (2012).

    CAS  PubMed  Google Scholar 

  14. 14.

    Craven, R. J. PGRMC1: a new biomarker for the estrogen receptor in breast cancer. Breast Cancer Res. 10, 113 (2008).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Ruan, X., Zhang, Y., Mueck, A. O., Willibald, M., Seeger, H., Fehm, T. et al. Increased expression of progesterone receptor membrane component 1 is associated with aggressive phenotype and poor prognosis in ER-positive and negative breast cancer. Menopause 24, 203–209 (2017).

    PubMed  Google Scholar 

  16. 16.

    Crudden, G., Loesel, R. & Craven, R. J. Overexpression of the cytochrome p450 activator hpr6 (heme-1 domain protein/human progesterone receptor) in tumors. Tumour Biol. 26, 142–146 (2005).

    CAS  PubMed  Google Scholar 

  17. 17.

    Cahill, M. A., Jazayeri, J. A., Catalano, S. M., Toyokuni, S., Kovacevic, Z. & Richardson, D. R. The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology. Biochim Biophys. Acta 1866, 339–349 (2016).

    CAS  PubMed  Google Scholar 

  18. 18.

    Ahmed, I. S., Rohe, H. J., Twist, K. E. & Craven, R. J. Pgrmc1 (progesterone receptor membrane component 1) associates with epidermal growth factor receptor and regulates erlotinib sensitivity. J. Biol. Chem. 285, 24775–24782 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Nakai, K., Hung, M. C. & Yamaguchi, H. A perspective on anti-EGFR therapies targeting triple-negative breast cancer. Am. J. Cancer Res 6, 1609–1623 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Mi, H., Muruganujan, A., Huang, X., Ebert, D., Mills, C., Guo, X. et al. Protocol Update for large-scale genome and gene function analysis with the PANTHER classification system (v.14.0). Nat. Protoc. 14, 703–721 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Oksvold, M. P., Thien, C. B., Widerberg, J., Chantry, A., Huitfeldt, H. S. & Langdon, W. Y. Serine mutations that abrogate ligand-induced ubiquitination and internalization of the EGF receptor do not affect c-Cbl association with the receptor. Oncogene 22, 8509–8518 (2003).

    CAS  PubMed  Google Scholar 

  22. 22.

    van Waarde, A., Rybczynska, A. A., Ramakrishnan, N. K., Ishiwata, K., Elsinga, P. H. & Dierckx, R. A. Potential applications for sigma receptor ligands in cancer diagnosis and therapy. Biochim Biophys. Acta 1848, 2703–2714 (2015).

    PubMed  Google Scholar 

  23. 23.

    Neubauer, H., Ma, Q., Zhou, J., Yu, Q., Ruan, X., Seeger, H. et al. Possible role of PGRMC1 in breast cancer development. Climacteric 16, 509–513 (2013).

    CAS  PubMed  Google Scholar 

  24. 24.

    Causey, M. W., Huston, L. J., Harold, D. M., Charaba, C. J., Ippolito, D. L., Hoffer, Z. S. et al. Transcriptional analysis of novel hormone receptors PGRMC1 and PGRMC2 as potential biomarkers of breast adenocarcinoma staging. J. Surg. Res. 171, 615–622 (2011).

    CAS  PubMed  Google Scholar 

  25. 25.

    Rohe, H. J., Ahmed, I. S., Twist, K. E. & Craven, R. J. PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding. Pharm. Ther. 121, 14–19 (2009).

    CAS  Google Scholar 

  26. 26.

    Clark, N. C., Friel, A. M., Pru, C. A., Zhang, L., Shioda, T., Rueda, B. R. et al. Progesterone receptor membrane component 1 promotes survival of human breast cancer cells and the growth of xenograft tumors. Cancer Biol. Ther. 17, 262–271 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ahmed, I. S., Rohe, H. J., Twist, K. E., Mattingly, M. N. & Craven, R. J. Progesterone receptor membrane component 1 (Pgrmc1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule. J. Pharm. Exp. Ther. 333, 564–573 (2010).

    CAS  Google Scholar 

  28. 28.

    Yoshitani, N., Satou, K., Saito, K., Suzuki, S., Hatanaka, H., Seki, M. et al. A structure-based strategy for discovery of small ligands binding to functionally unknown proteins: combination of in silico screening and surface plasmon resonance measurements. Proteomics 5, 1472–1480 (2005).

    CAS  PubMed  Google Scholar 

  29. 29.

    Will, E. A., Liu, X. & Peluso, J. J. AG 205, a progesterone receptor membrane component 1 antagonist, ablates progesterone’s ability to block oxidative stress-induced apoptosis of human granulosa/luteal cells†. Biol. Reprod. 96, 843–854 (2017).

    PubMed  Google Scholar 

  30. 30.

    Teakel, S. L., Ludescher, M., Thejer, B. M., Poschmann, G., Forwood, J. K., Neubauer, H. et al. Protein complexes including PGRMC1 and actin-associated proteins are disrupted by AG-205. Biochem Biophys. Res Commun. 524, 64–69 (2020).

    CAS  PubMed  Google Scholar 

  31. 31.

    Zhao, Y. & Ruan, X. Identification of PGRMC1 as a candidate oncogene for head and neck cancers and its involvement in metabolic activities. Front Bioeng. Biotechnol. 7, 438 (2019).

    CAS  PubMed  Google Scholar 

  32. 32.

    Sun, Q., Jackson, R. A., Ng, C., Guy, G. R. & Sivaraman, J. Additional serine/threonine phosphorylation reduces binding affinity but preserves interface topography of substrate proteins to the c-Cbl TKB domain. PLoS ONE 5, e12819 (2010).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Countaway, J. L., Nairn, A. C. & Davis, R. J. Mechanism of desensitization of the epidermal growth factor receptor protein-tyrosine kinase. J. Biol. Chem. 267, 1129–1140 (1992).

    CAS  PubMed  Google Scholar 

  34. 34.

    Feinmesser, R. L., Wicks, S. J., Taverner, C. J. & Chantry, A. Ca2+/calmodulin-dependent kinase II phosphorylates the epidermal growth factor receptor on multiple sites in the cytoplasmic tail and serine 744 within the kinase domain to regulate signal generation. J. Biol. Chem. 274, 16168–16173 (1999).

    CAS  PubMed  Google Scholar 

  35. 35.

    Shen, M., Jiang, Y. Z., Wei, Y., Ell, B., Sheng, X., Esposito, M. et al. Tinagl1 suppresses triple-negative breast cancer progression and metastasis by simultaneously inhibiting integrin/FAK and EGFR signaling. Cancer Cell. 35, 64–80 (2019). e7.

    CAS  PubMed  Google Scholar 

  36. 36.

    Nakai, K., Xia, W., Liao, H. W., Saito, M., Hung, M. C. & Yamaguchi, H. The role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 triple-negative breast cancer cells. Breast Cancer 25, 74–80 (2018).

    PubMed  Google Scholar 

  37. 37.

    Majorini, M. T., Manenti, G., Mano, M., De Cecco, L., Conti, A., Pinciroli, P. et al. cIAP1 regulates the EGFR/Snai2 axis in triple-negative breast cancer cells. Cell Death Differ. 25, 2147–2164 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Saha Roy, S. & Vadlamudi, R. K. Role of estrogen receptor signaling in breast cancer metastasis. Int J. Breast Cancer 2012, 654698 (2012).

    PubMed  Google Scholar 

  39. 39.

    Daniel, A. R., Hagan, C. R. & Lange, C. A. Progesterone receptor action: defining a role in breast cancer.Expert Rev. Endocrinol. Metab. 6, 359–369 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Cui, C., Li, S. & Wu, D. Znhit1 inhibits breast cancer by up-regulating PTEN to deactivate the PI3K/Akt/mTOR pathway. Life Sci. 224, 204–211 (2019).

    CAS  PubMed  Google Scholar 

  41. 41.

    Lee, Y. R., Chen, M., Lee, J. D., Zhang, J., Lin, S. Y., Fu T. M. et al. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science 364, eaau0159 (2019).

  42. 42.

    Lee, Y. R., Chen, M. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat. Rev. Mol. Cell Biol. 19, 547–562 (2018).

    CAS  PubMed  Google Scholar 

Download references


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

Author information




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.

Ethics declarations

Ethics approval and consent to participate

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).

Consent to publish

Not applicable.

Data availability

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

Competing interests

The authors declare no competing interests.

Funding information

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

Additional information

Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation