09:05pm Tuesday 21 November 2017

Turncoat Protein Regulates Sensitivity of Breast Cancer Cells to Drug, Providing New Target for Preventing Relapses, Finds Penn Study

The drug, lapatinib, activates the suppressor called FOXO, in HER2+ breast cancer cells, but then FOXO becomes a turncoat molecule, working with an epigenetic regulator that controls gene expression. This drug-triggered relationship induces the expression of the oncogene c-Myc, leading to reduced sensitivity to the cancer drug and eventually relapse. They published their cover article today in Cancer Cell.

“We found that an epigenetic pathway is crucial for growth of HER2+ cells and this epigenetic factor reduces sensitivity of the cancer cells to lapatinib, a HER2 inhibitor,” said senior author Xianxin Hua, MD, PhD, a professor of Cancer Biology. “We need to understand how the body initially responds to these drugs and why there is a relapse and devise a new tool to fix that.”

Human epidermal growth factor receptor 2 (HER2) is upregulated in a subset of human breast cancers. The HER2 pathway is mutated in many cancers, which drives tumors, but inhibitors of this pathway, such as lapatinib, have only limited success because cancer cells quickly adapt.

FOXO was normally thought of as the “good guy” molecule that controls cancerous cell growth, while c-Myc, the cancer-promoting molecule, the “bad guy.” However, FOXO becomes the agent that desensitizes cells to cancer drugs, so this “good guy” molecule is converted to a “bad guy,” during the treatment of the cancer cells with the anti-cancer drug.

“Now that we know about this triangle among FOXO, c-Myc, and the epigenetic pathway, we can stop c-Myc with an epigenetic inhibitor,” Hua said. “Multiple epigenetic regulators participate in the drug-desensitizing pathway, so they could serve as new targets to improve therapy for this type of cancer.”

The findings uncovered an adaptation pathway comprising the normally antagonizing molecules FOXOs and c-Myc, which are regulated by epigenetic compounds. Unraveling this complex interaction now gives researchers another point in the HER2 cancer pathway to hit. 

Coauthors are Smita Matkar, Paras Sharma, Shubin Gao, Buddha Gurung, Bryson W. Katona, Jennifer Liao, Abdul Bari Muhammad, Xiang-Cheng Kong, Lei Wang, Guanghui Jin, and Chi V. Dang, all from Penn.

This work was supported in part by the National Cancer Institute (R01-DK085121, 1-R01-CA-178856, 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’s Refunds for Research.

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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.9 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report‘s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $409 million awarded in the 2014 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2014, Penn Medicine provided $771 million to benefit our community.


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