An ErbB2/c-Src axis drives mammary tumorigenesis through metabolically directed translational regulation of Polycomb Repressor Complex 2 [array]

Perturbations in histone modifications alter transcription and promote carcinogenesis. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the mechanisms driving EZH2 overexpression are obscure and elucidating the role of PRC2 in breast cancer, which is highly heterogeneous, is challenging given its context-dependent oncogenic and tumor suppressive functions. Here, using genetically engineered mouse, PDX and cell line models, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 subunit overexpression via control of mRNA translation. In breast cancers initiated by the oncogene ErbB2, c-Src stimulates mitochondrial ATP production to suppress energy stress and permit sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumorigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis. We used microarrays to analyze transcriptional responses to c-Src ablation in the resulting c-Src-deficient mammary tumors. ErbB2-expressing tumors from mice without conditional Src alleles (hence expressing normal levels of c-Src) were used as the control. We extracted total RNA from four control tumors (MMTV-NIC/c-Src+/+) and four c-Src-deficient tumors (MMTV-NIC/c-SrcL/L) of equivalent size and subjected the RNA to Affymetrix microarray analysis.