Turncoat Protein Regulates Sensitivity of Breast Cancer Cells to Drug

A surprising, paradoxical relationship between a tumor suppressor molecule and an oncogene may be the key to explaining and working around how breast cancer tumor cells become desensitized to a common cancer drug, according to a new study published in Cancer Cell (2015; doi:10.1016/j.ccell.2015.09.005). The drug, lapatinib, activates a suppressor called FOXO in human epidermal growth factor 2 (HER2)-positive cancer cells, but then FOXO becomes a turncoat molecule that works with an epigenetic regulator to control gene expression.

The drug-triggered relationship induces the expression of the oncogene cMyc, which reduces sensitivity to lapatinib thereby leading to eventual relapse.

“We found that an epigenetic pathway is crucial for growth of HER2-positive 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 at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “We need to understand how the body initially responds to these drugs and why there is a relapse and devise a tool to fix that.”

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 a good-guy molecule that controls cancerous cell growth, while cMyc was the cancer-promoting bad-guy molecule. However, FOXO becomes the agent that desensitizes cells to cancer drugs, so this good-guy molecule turns into a bad guy during cancer treatment with lapatinib.

“Now that we know about this triangle among FOXO, cMyc, and the epigenetic pathway, we can stop cMyc 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 cMyc, which are regulated by epigenetic compounds. Unraveling this complex interaction now gives researchers another point in the HER2 cancer pathway to hit.

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