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

Raksha R. Bhat, Puja Yadav, Debashish Sahay, Dharmendra K. Bhargava, Chad J. Creighton, Sahar Yazdanfard, Ahmed Al-rawi, Vikas Yadav, Lanfang Qin, Sarmistha Nanda, Vidyalakshmi Sethunath, Xiaoyong Fu, Carmine De Angelis, Vihang A. Narkar, C. Kent Osborne, Rachel Schiff, Meghana V. Trivedi

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish
Pages (from-to)279-292
Number of pages14
JournalBreast Cancer Research and Treatment
Volume170
Issue number2
DOIs
StatePublished - 1 Jul 2018
Externally publishedYes

Keywords

  • Breast cancer
  • Drug resistance
  • Drug targets
  • GPR110
  • HER2
  • Tumorigenesis

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