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Downregulation of the PTEN tumor suppressor transcript is frequent in breast cancer and associates with poor prognosis and triple-negative breast cancer (TNBC) when comparing breast cancers to one another. Here we show that in almost all cases, when comparing breast tumors to adjacent normal ducts, PTEN expression is decreased and the PRC2-associated methyltransferase EZH2 is increased. We further find that when comparing breast cancer cases in large cohorts, EZH2 inversely correlates with PTEN expression. Within the highest EZH2 expressing group,  NOTCH  alterations are frequent, and also associate with decreased PTEN expression. We show that repression of  PTEN  occurs through the combined action of NOTCH ( NOTCH1  or  NOTCH2 ) and  EZH2  alterations in a subset of breast cancers. In fact, in cases harboring  NOTCH1  mutation or a  NOTCH2  fusion gene, NOTCH drives EZH2, HES-1, and HEY-1 expression to repress  PTEN  transcription at the promoter, which may contribute to poor prognosis in this subgroup. Restoration of PTEN expression can be achieved with an EZH2 inhibitor (UNC1999), a γ-secretase inhibitor (Compound E), or knockdown of  EZH2  or  NOTCH . These findings elucidate a mechanism of transcriptional repression of  PTEN  induced by  NOTCH1  or  NOTCH2  alterations, and identifies actionable signaling pathways responsible for driving a large subset of poor-prognosis breast cancers.

NOTCH and EZH2 collaborate to repress PTEN expression in breast cancer