Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance

• Published in: Breast cancer research : BCR Vol. 22; no. 1; p. 84
• Main Authors: Li, Li, Lin, Ling, Veeraraghavan, Jamunarani, Hu, Yiheng, Wang, Xian, Lee, Sanghoon, Tan, Ying, Schiff, Rachel, Wang, Xiao-Song
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 08.08.2020; BioMed Central; BMC
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Analysis; Animal models; Animals; Antibodies; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer genetics; Cancer therapies; Carrier Proteins - genetics; Cell fusion; Cell Line, Tumor; Cell survival; Chromosomes; Complementation; Dasatinib - administration & dosage; Drug Resistance, Neoplasm; Endocrine resistance; Endocrine therapy; ErbB-2 protein; ESR1-CCDC170; Estrogen Receptor alpha - genetics; Estrogen receptors; Estrogens; FDA approval; Female; Fulvestrant - administration & dosage; Genetic aspects; Growth factors; Health aspects; HER2; Humans; Immunoprecipitation; Kinases; Lapatinib - administration & dosage; Ligands; Luminal breast cancer; Lung cancer; Mice; Mice, Nude; Oncogene Proteins, Fusion; Phenols; Protein arrays; Proteins; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Signal Transduction; SRC; Src protein; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Tamoxifen; Tamoxifen - administration & dosage; Tumors; Western blotting; Xenograft Model Antitumor Assays; Xenografts; Endocrine resistance; ESR1-CCDC170; HER2; SRC; Luminal breast cancer
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-020-01325-3

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 has not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized. 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. 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. 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.