Project Grant K08CA301096

Federal Project Grant Summary

The Sloan-Kettering Institute for Cancer Research received a $246,362 Project Grant from the National Cancer Institute (NCI) under the Cancer Research Manpower program (CFDA 93.398), awarded June 12, 2026, with a completion date of May 31, 2031. This grant supports research investigating the evolutionary landscape of BRCA-associated breast cancer and its impact on endocrine therapy resistance. The project addresses a critical gap in cancer treatment, as approximately 60% of endocrine therapy resistance mechanisms remain unexplained in estrogen receptor-positive (ER+) breast cancers. The research will comprehensively characterize changes in BRCA2-associated ER+ breast cancers in response to endocrine therapy using patient tumor specimens and compare proliferative responses between BRCA2 carriers and noncarriers to determine if BRCA2 deficiency leads to accumulation of pathway alterations affecting estrogen receptor signaling.

The deliverables include comparative genomic and transcriptional profiling analyses of patient samples collected following preoperative endocrine therapy, assessment of tumor proliferative indices (KI67), and experimental studies examining direct effects of homologous recombination pathway alterations on estrogen receptor function using BRCA2-knockout versus wildtype ER+ breast cancer cell lines. These research activities leverage the Institute's existing patient-derived models and cell line collections to elucidate mechanisms of therapy resistance, with findings expected to explain a significant proportion of endocrine therapy-resistant cases and inform future treatment strategies for approximately 24% of primary breast cancers displaying homologous recombination deficiency.