Scientists Have Found the Cause of Reduced Drug Sensitivity in HER2-Positive Breast Cancer

The surprising, contradictory relationship between a tumor suppressor molecules and cancer gene may be the key to elucidating why breast cancer cells lose sensitivity to a common anticancer drug and work around it — researchers of the Perelman School of Medicine at the University of Pennsylvania reports the surprising discovery in the journal Cancer Cell.

The new study reveals that in HER2 + breast cancer cells, the drug, named Lapatinib, activates the suppressor-FOXO, which then became a traitor molecules, and wok with an epigenetic regulator that controls gene expression. This drug-triggered relationship induces the expression of oncogene c-Myc, thereby reducing the sensitivity of this cancer drug and resulting in a cancer recurrence.

“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.”

HER2-positive breast cancer cells have a gene mutation that causes them to produce too much HER2 (human epidermal growth factor receptor 2) protein, which promotes tumor growth. HER2 is upregulated in a part of breast cancers. HER2 signaling pathway is mutated in many cancers, driving the tumor, but because cancer cells can quickly adapt to this signaling pathway inhibitor such as lapatinib, thus it only achieved limited success.

FOXO was often regarded as a “good” molecules that controls the growth of cancer cells, and cancer-promoting molecule c-Myc were considered as a “bad guy.” Now, however, the researchers found that during the use of anti-cancer drugs in cancer treatment process, FOXO became the agent that make cells loss sensitive to anti-cancer drugs, so this “good guy” turned into a “bad guy.”

The results revealed an adaptive signaling pathway that is composed of the normal anti-cancer molecules FOXOs and c-Myc, which can be regulated by some of the epigenetic compounds. Clarifying this complex interaction now provides researchers another hit point in HER2 cancer signaling pathways.


An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis, Cancer Cell


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