| Summary: | The <i>hairless</i> (<i>HR</i>) gene encodes a transcription factor with histone demethylase activity that is essential for development and tissue homeostasis. Previous studies suggest that mutational inactivation of HR promotes tumorigenesis. To investigate HR mutations in breast cancer, we performed targeted next-generation sequencing using DNA isolated from primary breast cancer tissues. We identified <i>HR</i> somatic mutations in approximately 15% of the patient cohort (n = 85), compared with 23% for <i>BRCA2</i>, 13% for <i>GATA3</i>, 7% for <i>BRCA1</i>, and 3% for <i>PTEN</i> in the same patient cohort. We also found an average 23% <i>HR</i> copy number loss in breast cancers. In support of HR’s antitumor functions, HR reconstitution in <i>HR</i>-deficient human breast cancer cells significantly suppressed tumor growth in orthotopic xenograft mouse models. We further demonstrated that HR’s antitumor activity was at least partly mediated by transcriptional activation of <i>CELF2</i>, a tumor suppressor with RNA-binding activity. Consistent with HR’s histone demethylase activity, pharmacologic inhibition of histone methylation suppressed HR-deficient breast cancer cell proliferation, migration and tumor growth. Taken together, we identified HR as a novel tumor suppressor that is frequently mutated in breast cancer. We also showed that pharmacologic inhibition of histone methylation is effective in suppressing HR-deficient breast tumor growth and progression.
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