VCU news

By Leah Small

VCU Massey Cancer Center researchers have discovered why a molecule expressed with a protein known to drive 20 percent of breast cancers can lead to decreased effectiveness of a well-known targeted therapy.

They found that a molecule called microRNA-4728 prevents therapies targeting the HER2 protein from being effective. MicroRNA-4728 is co-expressed with HER2 in certain types of breast cancer cells, which means that when HER2 is overexpressed, so is microRNA-4728. Expression refers to the level of proteins in cells. 

These targeted therapies, HER2 inhibitors, are currently administered with chemotherapies to boost effectivity, but chemotherapies can be extremely toxic to noncancerous, normal cells, said Anthony Faber, Ph.D., assistant professor in the Philips Institute for Oral Health Research in the VCU School of Dentistry and a member of the Developmental Therapeutics research program at Massey Cancer Center.

The finding could lead to more effective combination therapies that inhibit the overexpression of HER2 and are relatively nontoxic, Faber said.

“If there were a targeted therapy combination that was as effective as HER2 inhibitors plus chemotherapy, which is the standard therapy for metastatic HER2 positive breast cancer right now, it would be preferred,” Faber said. “One of the biggest benefits of targeted therapies, like HER2 inhibitors, is they are considerably less toxic than the traditional chemotherapies because they target just the cancer cell.”

Faber and co-authors published a paper in the Proceedings of the National Academy of Sciences on Feb. 19 about the impact of microRNA-4728 expression on the efficacy of HER2 inhibitors in breast cancer.

The team found that when microRNA-4728 is overexpressed with HER2, it binds to estrogen receptors, which are another group of proteins found in breast cancer cells. MicroRNA-4728 reduces the expression of estrogen receptors. Estrogen receptors normally activate another protein called NOXA. Overexpressed microRNA-4728 therefore leads to abnormally low levels of NOXA.

NOXA’s primary function is to neutralize the harmful oncogene MCL-1, which the researchers have found to be an important survival factor for HER2 positive breast cancer.

“NOXA normally neutralizes MCL-1,” Faber said. “When MCL-1 is free it’s problematic and prevents HER2 inhibitors from killing the breast cancer cell.”

Faber said the researchers are planning clinical trials with new MCL-1 inhibitors in combination with HER2 inhibitors.

“Rational combination therapies are a promising direction in cancer therapeutic care,” Faber said.

Other VCU faculty authors on this study included Massey Cancer Center investigators Hisashi Harada, Ph.D., associate professor in the Philips Institute for Oral Health Research in the VCU School of Dentistry; Sosipatros Boikos, M.D., assistant professor in the VCU School of Medicine in the Division of Hematology, Oncology and Palliative Care; and Jennifer Koblinski, Ph.D., assistant professor of pathology in the VCU School of Medicine. The lead author is Konstantinos Floros, Ph.D., a former VCU researcher now at the National Institutes of Health. External collaborators included researchers at Memorial Sloan Kettering Cancer Center, Vall d’Hebron Institute of Oncology in Barcelona, and AbbVie pharmaceuticals, among others.

The research was funded with grants of $1.5 million from the National Cancer Institute, the Mary Kay Foundation and, in part, by Massey’s NCI Cancer Center Support Grant P30 CA016059 and other sources.