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

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

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzodiazepines / administration & dosage
Benzodiazepines / pharmacology
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Drug Resistance, Neoplasm
Drug Synergism
Epigenesis, Genetic* / drug effects
Female
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Neoplastic / drug effects
Humans
Lapatinib
Mice
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-myc / genetics*
Proto-Oncogene Proteins c-myc / metabolism
Quinazolines / administration & dosage
Quinazolines / pharmacology
Receptor, ErbB-2 / antagonists & inhibitors*
Receptor, ErbB-2 / genetics
Xenograft Model Antitumor Assays

Substances

DNA-Binding Proteins
Forkhead Transcription Factors
KMT2D protein, human
MYC protein, human
Neoplasm Proteins
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Quinazolines
Lapatinib
Benzodiazepines
molibresib
ERBB2 protein, human
Receptor, ErbB-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding