| First Author | Gala K | Year | 2018 |
| Journal | Oncogene | Volume | 37 |
| Issue | 34 | Pages | 4692-4710 |
| PubMed ID | 29755131 | Mgi Jnum | J:316063 |
| Mgi Id | MGI:6833854 | Doi | 10.1038/s41388-018-0273-5 |
| Citation | Gala K, et al. (2018) KMT2C mediates the estrogen dependence of breast cancer through regulation of ERalpha enhancer function. Oncogene 37(34):4692-4710 |
| abstractText | Estrogen receptor alpha (ERalpha) is a ligand-activated nuclear receptor that directs proliferation and differentiation in selected cancer cell types including mammary-derived carcinomas. These master-regulatory functions of ERalpha require trans-acting elements such as the pioneer factor FOXA1 to establish a genomic landscape conducive to ERalpha control. Here, we identify the H3K4 methyltransferase KMT2C as necessary for hormone-driven ERalpha activity and breast cancer proliferation. KMT2C knockdown suppresses estrogen-dependent gene expression and causes H3K4me1 and H3K27ac loss selectively at ERalpha enhancers. Correspondingly, KMT2C loss impairs estrogen-driven breast cancer proliferation but has no effect on ER- breast cells. Whereas KMT2C loss disrupts estrogen-driven proliferation, it conversely promotes tumor outgrowth under hormone-depleted conditions. In accordance, KMT2C is one of the most frequently mutated genes in ER-positive breast cancer with KMT2C deletion correlating with significantly shorter progression-free survival on anti-estrogen therapy. From a therapeutic standpoint, KMT2C-depleted cells that develop hormone-independence retain their dependence on ERalpha, displaying ongoing sensitivity to ERalpha antagonists. We conclude that KMT2C is a key regulator of ERalpha activity whose loss uncouples breast cancer proliferation from hormone abundance. |
