Journal
CANCER CELL
Volume 28, Issue 4, Pages 472-485Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2015.09.005
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Funding
- NIH [R01-DK085121, 1-R01-CA-178856, R01 DK097555]
- Caring for Carcinoid Foundation-AACR Grant Care for Carcinoid Foundation [11-60-33]
- ITMAT of the University of Pennsylvania
- University of Pennsylvania
- Pennsylvania Breast Cancer Coalition's Refunds for Research
- NIH/NIDDK Center for Molecular Studies in Digestive and Liver Diseases [P30DK050306]
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Human epidermal growth factor receptor 2 (HER2) is upregulated in a subset of human breast cancers. However, the cancer cells often quickly develop an adaptive response to HER2 kinase inhibitors. We found that an epigenetic pathway involving MLL2 is crucial for growth of HER2(+) cells and MLL2 reduces sensitivity of the cancer cells to a HER2 inhibitor, lapatinib. Lapatinib-induced FOXO transcription factors, normally tumor-suppressing, paradoxically upregulate c-Myc epigenetically in concert with a cascade of MLL2-associating epigenetic regulators to dampen sensitivity of the cancer cells to lapatinib. An epigenetic inhibitor suppressing c-Myc synergizes with lapatinib to suppress cancer growth in vivo, partly by repressing the FOXO/c-Myc axis, unraveling an epigenetically regulated FOXO/c-Myc axis as a potential target to improve therapy.
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