RODRIGO GONCALVES
Projetos de Pesquisa
Unidades Organizacionais
LIM/58 - Laboratório de Ginecologia Estrutural e Molecular, Hospital das Clínicas, Faculdade de Medicina
1 resultados
Resultados de Busca
Agora exibindo 1 - 1 de 1
- Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer(2018) LEI, Jonathan T.; SHAO, Jieya; ZHANG, Jin; IGLESIA, Michael; CHAN, Doug W.; CAO, Jin; ANURAG, Meenakshi; SINGH, Purba; HE, Xiaping; KOSAKA, Yoshimasa; MATSUNUMA, Ryoichi; CROWDER, Robert; HOOG, Jeremy; PHOMMALY, Chanpheng; GONCALVES, Rodrigo; RAMALHO, Susana; PERES, Raquel Mary Rodrigues; PUNTURI, Nindo; SCHMIDT, Cheryl; BARTRAM, Alex; JOU, Eric; DEVARAKONDA, Vaishnavi; HOLLOWAY, Kimberly R.; LAI, W. Victoria; HAMPTON, Oliver; ROGERS, Anna; TOBIAS, Ethan; PARIKH, Poojan A.; DAVIES, Sherri R.; LI, Shunqiang; MA, Cynthia X.; SUMAN, Vera J.; HUNT, Kelly K.; WATSON, Mark A.; HOADLEY, Katherine A.; THOMPSON, E. Aubrey; CHEN, Xi; KAVURI, Shyam M.; CREIGHTON, Chad J.; MAHER, Christopher A.; PEROU, Charles M.; HARICHARAN, Svasti; ELLIS, Matthew J.RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1-6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.