RNA sequencing of endocrine resistant breast cancer

*** This submission includes RNA data, with DNA files available under a different accession number*** Purpose: Endocrine therapy resistance remains the greatest challenge for treating hormone receptor positive breast cancer patients. We aim to identify molecular mechanisms underlying endocrine therapy resistance through in-depth genomic analysis of patient samples. Experimental Design: We collected tumors from 35 estrogen receptor positive breast cancer patients receiving endocrine therapy, of which 3 patients had intrinsic resistance and 19 patients developed acquired resistance. For each patient, multiple tumor specimens were collected during the course of treatment. We performed DNA whole exome sequencing and RNA sequencing on all tumor samples. DNA mutations, copy number alterations and RNA gene expression data were analyzed through supervised analyses comparing paired sensitive and resistant tumor samples to identify molecular features related to endocrine therapy resistance. Results: We identified mutations enriched in resistant tumors including ESR1 and GATA3. ESR1 D538G variant confers endocrine therapy resistance while E380Q variant confers hypersensitivity. We demonstrate that resistant tumors had distinct gene expression profiles and elevated signaling pathways including ER, HER2, GATA3, AKT, RAS and p63 signaling. Integrated analysis for individual patient highlighted the heterogeneity of endocrine therapy resistance mechanisms. Conclusions: Our results suggest that mechanisms underlying endocrine therapy resistance are highly heterogeneous with diverse changes in genomic and transcriptomic levels.