Xiaoting Zhang, PhD, associate professor in the Department of Cancer Biology at the University of Cincinnati College of Medicine, has received a $1.8 million, five-year, R01 award (R01CA197865) from the National Cancer Institute to continue breast cancer research focusing on the function of the protein MED1 on HER2-positive breast cancer.
MED1 is a protein often produced, or expressed, at abnormally high levels in breast cancer cells that when eliminated is found to stop cancer cell growth; HER2 breast cancer involves a protein called human epidermal growth factor receptor 2, which promotes the growth of cancer cells.
"Breast cancer remains one of the most common cancers and is one of the leading causes of death for women in the U.S.," says Zhang, who is a member of the Cincinnati Cancer Center and the UC Cancer Institute. "Recent studies have divided breast cancer into several subtypes based on gene expression of estrogen receptor, progesterone receptor and/or HER2. MED1 is an estrogen receptor activator that has been shown to play important roles in estrogen receptor-dependent functions in both mammary gland development and breast cancer.
"Interestingly, the MED1 gene is found very close to and amplified together with HER2, and the MED1 protein levels are highly linked to HER2 breast cancer. Additionally, we've found that MED1 functions as a key 'crosstalk' meeting point between the HER2 and estrogen receptor pathway in HER2 and estrogen receptor double positive breast cancer cells. However, the role and underlying molecular functions of MED1 in HER2-driven breast cancer development and spread is poorly understood.
"More discoveries about the relationship between MED1 and HER2 in breast cancers are necessary because the majority of estrogen receptor and HER2 positive breast cancer patients develop resistance to anti-estrogen and anti-HER2 therapies in a rather short period of time after their initial treatments. We hope this study provides new insight into simultaneously blocking the HER2 and estrogen receptor cellular pathway for the treatment of this type of breast cancer."
Using animal models that are genetically modified to overproduce or stop MED1 functions, researchers will study the development and spread of breast cancer. This will be the first time that researchers examine how genes that amplify with HER2 play a role in HER2-driven tumor formation. They will focus on investigating the function of MED1 and its key pathways in cancer stem cell formation of HER2-driven tumors, with a goal of intervening for possible cancer therapy.
Researchers will also test the therapeutic potential of targeting MED1 and its key pathway components through an RNA nanodelivery system. Nanodelivery for this study involves using RNA nanoparticles to deliver highly targeted chains of RNAs (RNA aptamers and siRNAs) specifically into human breast cancer cells to potentially stop cancer growth. RNA nanoparticles are stable and versatile and prompt little or no immune response, making them most suitable for therapeutic applications. Researchers in Zhang's lab will partner with former UC faculty member Peixuan Guo, PhD, who is now the director of the Cancer Nanotechnology Platform Partnership Program: RNA Nanotechnology for Cancer Therapy at the University of Kentucky Mackey Cancer Center, to accomplish this.
"Our long-term goal is to understand the role of regulating proteins, particularly MED1 and HER2, in breast cancer and to test the efficacy of targeting them with the ultimate goal of providing new insights and potential therapeutic targets for better treatment of the disease," Zhang says. "Findings from this study could mean exciting new therapies, especially for patients with HER2 and estrogen receptor positive breast cancer."
"I truly appreciate the tremendous research and administrative support I have received over the years," he continues. "Without it, I surely would not be able to get this far and achieve this key milestone in my research career. I would like to particularly thank Jun-Lin Guan, PhD, (Francis Brunning Chair and professor in the Department of Cancer Biology), and Susan Waltz, PhD, (professor in the department), for the Brown Bag Meetings and College of Medicine study section they organized, as well as the highly enthusiastic participation of our cancer biology faculty. All of their highly insightful comments and critiques truly made a difference in reshaping the grant and getting it funded in its first submission."
"I am happy and gratified that Dr. Zhang's hard work and persistence finally paid off," says Guan says. "This innovative study is expected to provide significant insights into the mechanisms of MED1 in the regulation of the growth of cancer stem cell formation and metastasis of an especially difficult to treat subtype of breast cancer.
"Importantly, Dr. Zhang and his collaborators will further develop and test RNA-based nanotherapeutics for the treatments of this subtype of breast cancer using their recently-generated, novel and clinically more relevant mouse models."
"I would also like to take this opportunity to especially thank the Cincinnati Cancer Center and Ohio Cancer Research Associates (OCRA) for their pilot grant and seed money during this difficult funding environment, which enabled us to generate much needed preliminary data for the application of this grant." Zhang says, adding that his laboratory has previously been supported by the U.S. Department of Defense, the American Cancer Society, the Komen for the Cure Foundation, the American Heart Association, Ride Cincinnati and the University of Cincinnati Cancer Institute.