Baylor College of Medicine Houston, Texas
Professor, Medicine and Molecular and Cellular Biology
Overcoming resistance to therapies to prevent metastasis of estrogen receptor-positive breast cancer
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.
Dr. Fuqua and her team previously discovered that mutations in the ESR1 gene are the major drivers in the development of drug resistance leading to metastasis. More recently, they demonstrated that ESR1 mutations alter cell cycle checkpoints that normally regulate cell growth. Inhibiting these checkpoints in the laboratory significantly blocks metastasis. She and her team also revealed that PARP inhibitors, which target a DNA repair defect commonly seen in BRCA-associated and triple negative breast cancer, reduce the growth of ESR1-mutated tumors.
ESR1 mutations cause the cancer cells to multiply so quickly that they make mistakes—their DNA gathers mutations, which subsequently activates a DNA repair response. Understanding this mechanism unlocks new therapeutic vulnerabilities, potentially making ESR-1 driven metastatic tumors more susceptible to a combination of drugs that target DNA damage response and next-generation endocrine therapies. In the coming year, the team will test newly approved ER-targeted therapies called SERDs (selective estrogen receptor degraders) in combination with PARP inhibitors in laboratory models and study their interaction mechanism.
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.
2014
The Kendra Scott Foundation Award in Honor of Holley Rothell Kitchen
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