Abstract P1-07-07: Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of estrogen-receptor positive breast cancers

Abstract

Abstract The crucial role of gene fusions in epithelial tumorigenesis has been recently appreciated by several milestone discoveries, but no significant recurrent translocations have yet been found in the vast majority of breast cancers that express the estrogen receptor (ER). While a majority of ER+ tumors can be effectively treated by endocrine therapy, tumors of the luminal B subtype are more aggressive and endocrine therapy-resistant. Further, the molecular blueprint of these aggressive tumors is poorly understood. Thus, characterizing the genetic alterations underlying the more aggressive forms of ER+ breast cancer is of critical significance in breast cancer management. In this study, by large-scale analyses of breast cancer transcriptome and copy number alterations, we identified recurrent rearrangements between estrogen receptor gene, ESR1 and its neighbor gene, CCDC170, which are enriched in the more aggressive and endocrine-resistant luminal-B tumors. Further screening of 200 ER+ breast tumor tissues by RT-PCR identified eight ESR1-CCDC170 positive tumors. The genomic rearrangements underlying these fusions were verified by genomic PCR and capillary sequencing. CCDC170 encodes a protein with unknown function. The observed fusion joins the 5’-untranslated region of ESR1 upstream to the coding region of CCDC170, enabling the expression of N-terminally truncated CCDC170 (ΔCCDC170) under the promoter of the ESR1 gene. Consistent with the behavior of luminal B tumors, forced expression of ΔCCDC170 in ER+ breast cancer cells leads to markedly increased cell motility, invasiveness and anchorage-independent growth, and reduced endocrine sensitivity in vitro, as well as enhanced xenograft tumor formation and reduced endocrine sensitivity of the tumors in vivo. When introduced into benign breast epithelial cells, ΔCCDC170 impairs acini morphogenesis and enhances cell motility and invasiveness. Further, Knockdown of the endogenous ESR1-CCDC170 fusion variant expressed in HCC1428 cells potently inhibited cancer cell proliferation and migration, which can be rescued by forced expression of this fusion. Mechanistic studies suggest that ΔCCDC170 engages Gab1 signalosome to potentiate growth factor signaling and enhance cell motility. The augmented growth factor signaling driven by ΔCCDC170 appears to be sustained even after withdrawal of serum, and is not affected by endocrine treatment. Together, this study identified neoplastic ESR1-CCDC170 fusions in a more aggressive subset of ER+ breast cancer, which also suggests a new role of ER in breast tumorigenesis by contributing its promoter to an oncogene. Citation Format: Jamunarani Veeraraghavan, Ying Tan, Xi-Xi Cao, Jin-Ah Kim, Xian Wang, Dean P Edwards, Alejandro Contreras, Susan G Hilsenbeck, Eric C Chang, Rachel Schiff, Xiao-Song Wang. Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of estrogen-receptor positive breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-07.