Turncoat Protein Regulates Sensitivity Of Breast Cancer To Drug

Turncoat Protein Regulates Sensitivity Of Breast Cancer 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, researchers have found.
 
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. The findings were published in Cancer Cell.
 
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," senior author Xianxin 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.
 
Based on material originally posted by University of Pennsylvania School of Medicine.