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GPCRs profiling and identification of GPR110 as a potential new target in HER2+ breast cancer

  • Preclinical study
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Abstract

Purpose

G protein-coupled receptors (GPCRs) represent the largest family of druggable targets in human genome. Although several GPCRs can cross-talk with the human epidermal growth factor receptors (HERs), the expression and function of most GPCRs remain unknown in HER2+ breast cancer (BC). In this study, we aimed to evaluate gene expression of GPCRs in tumorigenic or anti-HER2 drug-resistant cells and to understand the potential role of candidate GPCRs in HER2+ BC.

Methods

Gene expression of 352 GPCRs was profiled in Aldeflur+ tumorigenic versus Aldeflur− population and anti-HER2 therapy-resistant derivatives versus parental cells of HER2+ BT474 cells. The GPCR candidates were confirmed in 7 additional HER2+ BC cell line models and publicly available patient dataset. Anchorage-dependent and anchorage-independent cell growth, mammosphere formation, and migration/invasion were evaluated upon GPR110 knockdown by siRNA in BT474 and SKBR3 parental and lapatinib+ trastuzumab-resistant (LTR) cells.

Results

Adhesion and class A GPCRs were overexpressed in Aldeflur+ and anti-HER2 therapy-resistant population of BT474 cells, respectively. GPR110 was the only GPCR overexpressed in Aldeflur+ and anti-HER2 therapy-resistant population in BT474, SKBR3, HCC1569, MDA-MB-361, AU565, and/or HCC202 cells and in HER2+ BC subtype in patient tumors. Using BT474 and SKBR3 parental and LTR cells, we found that GPR110 knockdown significantly reduced anchorage-dependent/independent cell growth as well as migration/invasion of parental and LTR cells and mammosphere formation in LTR derivatives and not in parental cells.

Conclusion

Our data suggest a potential role of GPR110 in tumorigenicity and in tumor cell dissemination in HER2+ BC.

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Acknowledgements

This work was supported in part by the Department of Defense BCRP Grants W81XWH-14-1-0340 and W81XWH-14-1-0341; NIH Grants CA125123, P50 CA058183, HL129191, and CA186784-01; Stand Up To Cancer (SU2C-AACR-DT0409), Welch Foundation endowment in Chemistry and Related Sciences (L-AU-0002), as well as Grants from American Association of Colleges of Pharmacy and UH Small Grants Program. None of the funding agencies had any role in the design, analysis, or reporting of the analyses.

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Authors and Affiliations

  1. Department of Pharmacy Practice and Translational Research, University of Houston, 4849 Calhoun St, Houston, TX, 77204, USA

    Raksha R. Bhat, Puja Yadav, Debashish Sahay, Dharmendra K. Bhargava, Sahar Yazdanfard, Ahmed Al-rawi & Meghana V. Trivedi

  2. Department of Medicine, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Chad J. Creighton, C. Kent Osborne, Rachel Schiff & Meghana V. Trivedi

  3. Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA

    Vikas Yadav & Vihang A. Narkar

  4. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    Lanfang Qin, Sarmistha Nanda, Vidyalakshmi Sethunath, Xiaoyong Fu, Carmine De Angelis, C. Kent Osborne, Rachel Schiff & Meghana V. Trivedi

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  1. Raksha R. Bhat
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Correspondence to Meghana V. Trivedi.

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Bhat, R.R., Yadav, P., Sahay, D. et al. GPCRs profiling and identification of GPR110 as a potential new target in HER2+ breast cancer. Breast Cancer Res Treat 170, 279–292 (2018). https://doi.org/10.1007/s10549-018-4751-9

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