Cooperation between at least two key genes–HER2 and MED1–drives growth, spread, and treatment resistance in one particularly aggressive type of breast cancer, according to a new study from University of Cincinnati (UC). Targeting this gene, as well as HER2, could augment treatment for some patients and help prevent drug resistance, their research suggests.
One of the best-known molecular drivers of breast cancer is HER2. However, about a dozen genes, including one called MED1, are located within the same chromosomal region where HER2 is over-expressed some in breast cancers. Until now, it was not known whether any of these other genes played a role in the development of HER2 positive breast cancer.
To start to answer this question, the UC team created an animal model that overproduces both HER2 and MED1 in the mammary gland. The researchers found that the two genes can in fact work with each other to further speed up protein production, which in turn promotes rapid cell multiplication, movement and invasion to spread cancer, and treatment resistance.
This study is published in this week’s online edition of the journal Cell Reports.
“According to the American Cancer Society’s estimate, over 280,000 new cases of invasive breast cancer will be diagnosed in women in 2021,” says Xiaoting Zhang, Ph.D., a professor in UC’s Department of Cancer Biology and director of the Breast Cancer Research Program, who led this research. “Like many other cancers, breast cancer cells are fueled by mutations and overproduction of ‘driver’ genes, which lead the process of cancer development.”
HER2 (human epidermal growth factor receptor 2), accounts for about 20% of all human breast cancer cases. These tumors tend to be more aggressive than other types of breast cancer, and while there are targeted therapies for them, unwanted side effects and treatment resistance often occur, causing relapse.
Previous research has shown that MED1 (mediator of RNA polymerase II subunit 1) is also amplified and has a role in treatment resistance in another type of breast cancer – ER+ (estrogen receptor positive). Now this UC study suggests MED1 also plays a role in HER2+ breast cancers.
“Our findings suggest that targeting MED1, alone and in combination with current therapies, could be an effective treatment strategy for nearly 90% of breast cancer patients in clinics and combat treatment resistance to two widely used breast cancer therapies,” Zhang says.
Zhang and his team have already developed a treatment targeting MED1 in tumors using RNA nanotechnology, and have observed positive outcomes.
Besides highlighting the role of MED1 in HER2 positive tumors, this research has also generated a new mouse model – MED1 mammary specific overexpression mice. Yongguang Yang, Ph.D., first author on this study and a research associate in Zhang’s lab, says “This new animal model we created has a wide range of future applications and will allow us to continue to study basic molecular mechanisms of this type of breast cancer to find and test new therapies.”