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Cancer Cell. 2015 Oct 12;28(4):472-485. doi: 10.1016/j.ccell.2015.09.005.

An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis.

Author information

1
Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA.
2
Xiamen University College of Medicine, Xiangan District, Xiamen 361006, PR China.
3
Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
4
Department of Medicine, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA.
5
Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA. Electronic address: huax@mail.med.upenn.edu.

Abstract

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.

PMID:
26461093
PMCID:
PMC4748715
DOI:
10.1016/j.ccell.2015.09.005
[Indexed for MEDLINE]
Free PMC Article

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