NOTCH and EZH2 collaborate to repress PTEN expression in breast cancer

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.