2019 Discovery of the Year presented to Dr. Zhijie “Jason” Liu
Mays Cancer Center Annual Report
New finding unlocks molecular secret behind breast cancer
While significant advancements have been made in breast cancer research, the disease still takes the lives of more than 40,000 women in America each year. One out of every eight women in the United States will develop invasive breast cancer that is usually therapy resistant during her lifetime.
In 70 percent of these women, estrogen and its estrogen receptor a (ERa) are key players in the disease, and ERa is a well-known breast cancer marker. Keeping this endocrine signaling function low through endocrine therapy is currently the best treatment for ER positive breast cancer. Yet, after five years, hormonal treatment stops working in more than 30 percent of these patients and the disease returns. This phenomenon is called endocrine resistance in the clinical field.
Zhijie “Jason” Liu, Ph.D., assistant professor of molecular medicine and CPRIT Scholar in Cancer Research, earned the 2019 Discovery of the Year Award from the Mays Cancer Center for his research studying mechanisms of endocrine resistance in breast cancer and the role of estrogen receptor-bound enhancers.
The Cancer Prevention and Research Institute of Texas (CPRIT) awarded $2 million to UT Health San Antonio in 2015 to help fund the recruitment of Dr. Liu from the University of California at San Diego’s Howard Hughes Medical Institute.
Dr. Liu, who set up his lab in San Antonio in February 2016, said his research team is focusing on studying both therapy resistance and metastasis in breast cancer using cellular models, patient-derived xenograft (PDX) models (which are models of cancer where tissue or cells from a patient’s tumor are implanted into an immune-deficient or humanized mouse), and transgenic mouse models (which are genetically engineered mouse models) that can spontaneously develop breast cancer, including primary tumors at the mammary glands as well as secondary metastatic tumors in the lungs, liver and brain.
“These transgenic mouse models will allow us to perform molecular biology and systems biology research to understand the gene regulation mechanism in vivo, not only just the knowledge that we have gained on growing cells in dishes,” he said. “This allows us to see the real and big picture. We can do deep sequencing to understand the DNA regulatory elements, especially enhancers, and gene expression levels genome wide. We are not trying to understand just one tree in the forest. We want to understand the entire forest.”
Published in August 2019 in the Molecular Cell journal, his research paper is titled “A Non-canonical Role of YAP/TEAD Is Required for Activation of Estrogen-Regulated Enhancers in Breast Cancer.” Dr. Liu explains, “We found something exciting that people didn’t notice before. This finding was initiated during our studies of the functional mechanisms of ERa-bound enhancers, which are functional elements on DNA to mediate the gene regulation effects from estrogen and its receptor ERa.
“Surprisingly, we found YAP/TEAD, which were known as a functional mediator inside the nuclei for Hippo signal, also work together with ERa on ERa-bound enhancer sites, and these interactions are required for estrogen signal function. We are currently continuing to figure out how YAP/TEAD affect gene regulation that drives tumor invasive or therapy-resistant progression.”
Patients who have ERa positive breast cancer are prescribed endocrine therapy, which is hormone therapy designed to slow or stop the growth of hormone-sensitive tumors by blocking the body’s ability to produce hormones or inhibit the effects of hormones on breast cancer cells.
“The major problem with endocrine therapy is that it will work in the beginning but stops later on. That is the major topic we are concentrating on in my lab,” he said. “When we were studying the function of ERa-bound enhancers, we found ERa works with many other partners which we did not know well before. Using some cutting-edge proteomics technology, we identified YAP/TEAD as novel ERa-interacting cofactors. We were the first to find the Hippo components can come on to the ERa enhancer and regulate the function of ERa enhancers.”
Tim H. M. Huang, Ph.D., deputy director of the Mays Cancer Center, and Patrick Sung, D.Phil., scientific program leader for the center’s Cancer Development and Progression, nominated Dr. Liu for the research award. In their nomination, they stated: “Dr. Liu and his trainees unveil a non-canonical function of these nuclear factors in gene expression germane for understanding breast cancer development and progression. Specifically, through proteomics and other molecular analyses, a novel function of YAP1 and TEAD4 as coregulators of estrogen/ERa responsive genes is found.
“Importantly, YAP and TEAD act as critical scaffolding elements in assembling a higher order protein complex needed for enhancer activity. These findings thus reveal a new role of YAP and TEAD in gene expression via an enhancer-specific function, and they also contribute toward delineating the basis of cancer cell growth that is driven by the expression of estrogen/ERa responsive genes. Moreover, this study highlights the potential of targeting YAP/TEAD in the treatment of ERa-positive breast cancer.”
Dr. Liu said that all means cancer signaling is much more complicated than was once thought. “We have a lot more work to do. How can we use this knowledge to develop new drugs? Now that we know that YAP and TEAD are not only known key drivers for the Hippo signaling pathway but also function non-canonically with the estrogen receptor to regulate the estrogen-regulated gene program. This finding suggests that we need to create more specific drugs to target one side of YAP/TEAD function if we want to stop estrogen signaling and not affect Hippo signaling in breast cancer.”
While he emphasizes his research is in the early stage, Dr. Liu said he is very appreciative of receiving the Discovery of the Year Award from the cancer center. “It means a lot to me as a young principal investigator.”
“Dr. Huang brought me here. I have a lot of collaborators here: Rong Li, Ph.D.; Alexander J.R. Bishop, D.Phil.; and Dr. Sung. I’ve learned a lot from them. They are role model scientists to me. Being surrounded by such dedicated researchers motivates me to take my research to the next level. In my lifetime, I hope to find drugs that will control metastatic or therapy-resistant cancers.”
