@article{1a2afc88ff6c4019b8c39d2b1b07ba8e,
title = "An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis",
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.",
author = "Smita Matkar and Paras Sharma and Shubin Gao and Buddha Gurung and Katona, {Bryson W.} and Jennifer Liao and Muhammad, {Abdul Bari} and Kong, {Xiang Cheng} and Lei Wang and Guanghui Jin and Dang, {Chi V.} and Xianxin Hua",
note = "Funding Information: We thank Drs. Peter Zhou and Yong Wan for critically reading the manuscript, Brian Bakke and Haoren Wang for technical assistance, and Ashley Banks for editing the manuscript. This work was supported in part by grants from the NIH (R01-DK085121, 1-R01-CA-178856, and R01 DK097555), Caring for Carcinoid Foundation-AACR Grant Care for Carcinoid Foundation (11-60-33), a pilot grant from ITMAT of the University of Pennsylvania, as well as a sarcoma pilot grant from University of Pennsylvania, and a grant from Pennsylvania Breast Cancer Coalition{\textquoteright}s Refunds for Research. This work was also supported in part by the NIH/NIDDK Center for Molecular Studies in Digestive and Liver Diseases (P30DK050306) and its core facilities (Molecular Biology/Gene Expression Core). We thank Austin Thiel for help in assembling the epigenetic shRNA library and John Tobias for statistical analysis. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = oct,
day = "12",
doi = "10.1016/j.ccell.2015.09.005",
language = "English (US)",
volume = "28",
pages = "472--485",
journal = "Cancer cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}