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

Smita Matkar, Paras Sharma, Shubin Gao, Buddha Gurung, Bryson W. Katona, Jennifer Liao, Abdul Bari Muhammad, Xiang Cheng Kong, Lei Wang, Guanghui Jin, Chi V. Dang, Xianxin Hua

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number2143
Pages (from-to)472-485
Number of pages14
JournalCancer Cell
Volume28
Issue number4
DOIs
StatePublished - Oct 12 2015
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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