Researchers have identified the signaling pathway that is overactivated in estrogen receptor (ER)-positive breast cancer cells that are resistant to hormone therapies such as tamoxifen, aromatase inhibitors, or fulvestrant.
Resistance to hormone therapy is reported in almost half of ER-positive breast cancer patients and no cure is currently available. The fact that the pathway, called Notch, is a drug target creates hope for a new therapy.
The findings “provide a new therapeutic target against hormone therapy-resistant breast cancers and a companion test to identify tumors that would become resistant” said research leader Mathieu Lupien, PhD, of the Ontario Cancer Institute, the research arm of the Princess Margaret Cancer Centre, and an assistant professor in the Department of Medical Biophysics, University of Toronto in Canada. He specializes in epigenetics of hormone-dependent cancers—the study of nongenetic determinants of cellular identity that can also be altered to initiate or modify disease.
“In studying the epigenetics of hormone therapy resistance, we discovered that breast cancer cells behave like a chameleon. Indeed, as the chameleon changes its skin color to camouflage itself and evade predators, breast cancer cells change the appearance of their DNA through epigenetics to evade, in this case, hormone therapy,” said Lupien. In so doing, hormone therapy-resistant breast cancer cells highlight regions of their DNA related to the Notch pathway.
At the molecular level, the research team characterized the epigenetic appearances of the DNA of drug-resistant and drug-responsive breast cancer cells. The team discovered that the Notch signaling pathway plays the predominant role in drug-resistant breast cancer cells even if cells remain positive for ER. Their findings were published in PNAS (2013; doi:10.1073/pnas.1219992110).
This highly promising discovery could rapidly translate into improved patient outcomes in the clinic. “Drugs against the Notch pathway are available,” Lupien noted. The key will be to test the efficacy of these drugs against hormone therapy resistance in breast cancer.