Abstract

Background Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance have not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized.Methods The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays.Results Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib.Conclusion ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.Competing Interest StatementDr. Rachel Schiff receives research funding from AstraZeneca, GlaxoSmithKline, Gilead Sciences, and PUMA Biotechnology, outside of this project; and is a consulting/advisory committee member for Macrogenics, and Eli Lilly. The other coauthors do not have competing financial interests.AbbreviationsABCATP-binding cassetteAIsaromatase inhibitorsBiFCBimolecular Fluorescence ComplementationCCDC170coiled-coil domain containing 170CSScharcoal-stripped serumΔCCDC170truncated CCDC170 proteinsE2estradiolERestrogen receptorFDAFood and Drug Administration4-OHT4-hydroxytamoxifenORFopen reading frameRPPAReverse phase protein array analysisSERDsselective ER down-regulatorsSERMsselective ER modulatorssiRNAsmall interfering RNASMCstructural maintenance of chromosomesTPERTissue Protein Extraction ReagentView Full Text