Titles and Affiliations
Professor, Medicine and Molecular and Cellular Biology
Research area
Overcoming resistance to therapies to prevent metastasis of estrogen receptor-positive breast cancer.
Impact
When breast cancer spreads to other tissues, it often loses its sensitivity to anti-cancer drugs. For the most common type of breast cancer, estrogen receptor (ER)-positive, mutations in the ESR1 gene are a cause of resistance to anti-estrogen therapies called aromatase inhibitors (AI) and promote metastasis. Dr. Fuqua’s research is focused on finding ways to counter the effect of mutated ESR1 to improve treatment and prevention strategies for metastatic breast cancer (MBC). Her work could lead to new, more effective ways of managing ER-positive MBC.
Progress Thus Far
Dr. Fuqua and her team previously discovered that mutations in the ESR1 gene are the major drivers in the development of AI resistance leading to metastasis. Their research has also uncovered a key weakness in these cancers: they are highly sensitive to drugs that target DNA repair, like FDA-approved PARP inhibitors. When combined with standard hormone therapy in laboratory models, PARP inhibitors significantly reduce tumor growth compared to standard therapy alone, and results suggest they may prevent further spread. Similar results were seen when paired with a newer generation of hormone-blocking drugs, such as estrogen receptor degraders. Separately, the team has found that as these tumors evolve and spread, they undergo widespread changes in how genes are switched on and off. Among these changes, they have identified a set of genes whose activity can help predict which patients are more likely to develop metastatic disease.
What’s next
Dr. Fuqua and her team will investigate why ESR1-mutant tumors are so vulnerable to PARP inhibitors. They will also test a new class of drugs that target the machinery controlling which genes are turned on or off in these tumors to see whether blocking this process can stop cancer cells from spreading. Together, these studies aim to generate enough evidence to support a future clinical trial testing these approaches in patients with ESR1-mutant metastatic breast cancer.
“If not for BCRF funded research, I would have been more apprehensive with my own breast cancer diagnosis, but instead I am filled with optimism that we will conquer metastatic progression.”
Biography
Dr. Fuqua has bachelor’s and master’s degrees from the University of Houston. She received a PhD in Cancer Biology from the University of Texas Graduate School of Biomedical Science. She is a Professor of Medicine and Molecular and Cellular Biology at Baylor College of Medicine. The main goal of her research is to determine the role of specific somatic mutations in estrogen receptor alpha, called K303R and Y537N, in the clinical problem of hormone resistance. Dr. Fuqua was the first to discover alternatively spliced transcriptional isoforms and somatic mutations in breast tumors. She has determined that the K303R mutation alters many aspects of hormone action, including binding to co-regulatory proteins, enhanced stability, estrogen hypersensitivity, response to tamoxifen, and resistance to the aromatase inhibitor anastrozole. Her team discovered the Y537N mutation, a constitutionally active receptor in metastatic tumors. A major goal of her laboratory is to develop novel therapeutics to target these alterations in ER alpha to restore hormone sensitivity, as well as to identify other novel mechanisms of resistance.
