The Cancer Center’s Xiaoting Zhang, PhD, said antiestrogen therapy is used for about 75% of breast cancers, but relapse and treatment resistance occur in about half of these patients at some point.

Zhang and his colleagues previously identified a protein called MED1 that is produced in much higher levels in 40% to 60% of breast cancers. MED1 plays key roles in mediating treatment resistance with estrogen receptors (ERs) and the protein HER2, but researchers did not know how it was produced at such a high level to cause treatment resistance.

“With this research, we mainly tried to understand why MED1 is expressing so high in these treatment-resistant breast cancers,” said Zhang, professor and John and Gladys Strauss Endowed Chair in the Department of Cancer Biology in UC’s College of Medicine.

The researchers focused on microRNA, small strands of noncoding genetic material within cells that regulate the expression of different genes. The discovery of microRNA has been awarded the Nobel Prize in Physiology or Medicine in 2024.

“These noncoding RNAs, including microRNAs, are the future,” Zhang said. “Noncoding regions occupy approximately 90% of the human genome — and people used to think they are all junk — but now people realize that these noncoding RNAs transcribed actually play crucial roles such as regulating proteins’ expression and function.”

The team found that a strand of microRNA called miR-205 has a sequence that can regulate the production of MED1. They further analyzed the human breast cancer database to confirms an inverse correlation between miR-205 and MED1 levels.

“So if MED1 is high, miR-205 is actually low. Essentially, this microRNA will block the production of MED1,” Zhang said. “Then we found they also correlate with treatment outcomes. So if you have low miR-205, now you have high MED1, and the cancer can actually be resistant to the treatment, and you have poor treatment outcomes.”

Researchers also found that miR-205 regulates the protein HER3 in addition to MED1. Part of the four-member HER family of proteins, HER3 is known to work with HER2 to play a role in treatment resistance. Specifically, researchers found that HER3 can regulate the activation of MED1 proteins.

“We not only have more MED1, but more active MED1, so it’s like a double regulation there with this miR-205 regulation of both MED1 and HER3,” Zhang said. “Subsequent studies using in vitro human breast cancer cell lines and in vivo animal models have further confirmed our findings and its functional significance.”

While more research is needed, Zhang said boosting levels of miR-205 could be a different and potentially more effective way to overcome treatment-resistant breast cancers by blocking MED1 production and activity.

Supported by UC’s Venture Lab, Zhang and his startup RNA Nanotherapeutics have patented RNA nanoparticle technology to deliver treatment to breast cancer cells that target MED1 directly. Recent completion of the STTR Phase 1 studies has shown this treatment is both effective in animal models and safe, even at 10 times the current effective dose. Zhang said the technology could easily be adapted to boost levels of miR-205.

“We are very interested in different RNAs and how they could fit into this because we have this RNA nanotherapeutics approach that can easily include different RNAs into the system and test them out using our already established approaches,” he said.

Zhang leads the Cancer Center’s Breast Cancer Research Program, and the next phase of this research will utilize patient-derived breast cancer samples obtained through patient donations at the Cancer Center. With support from the Ride Cincinnati Foundation, the Waddell Family Fund and the Cancer Center, the program has used these donated samples to develop over 20 human breast cancer patient-derived organoids — three-dimensional tissue cultures — and four animal models that will be used to test this new treatment.

“We already have deposited these models in the Cancer Center’s Biospecimen Shared Resource right here, and all of our researchers can go request those unique and precious resources that are very hard to get. Only a few places in the U.S. have it,” Zhang said. “Our local patients very generously agreed to donate these tumor samples, and I think it’s very important and could have implications since every breast cancer is different. If you use local patient samples, you may have more impact for the future treatment tailored for the local patient population as well.”

Stay connected with the Cancer Center

Study coauthors include UC's Bin Ouyang, Mingjun Bi, Mahendra Jadhao and Gregory Bick.

Featured photo at top of Zhang working in his laboratory. All photos/Andrew Higley/UC Marketing + Brand.