Author ORCID Identifier
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Todd W. Miller
Breast cancer is among the most frequently diagnosed cancers in the U.S. and is one of the leading causes of cancer-related mortalities, second to lung cancer. Estrogen receptor alpha-positive (ER+) breast cancer accounts for 2/3 of diagnosed cases. Patients diagnosed with this subtype of breast cancer typically undergo endocrine therapy that aims to mitigate the growth-promoting effects of estrogen/ER. While therapies are effective, 1/3 of patients will experience recurrence. To begin addressing this drug-resistant patient population, we investigated potential drug targets involved in response to treatment.
Coregulators have been implicated in the regulation of ER transcriptional activity and subsequently affecting the success of treatment with endocrine therapies. Using the mutant biotin ligase labeling system TurboID, we profiled the ER interactome in response to estrogen to identify novel regulators of ER activity. By identifying novel targets, we aim to identify new therapeutically targetable vulnerabilities.
Upon cancer recurrence with endocrine therapies, patients are often switched to an alternative endocrine therapy combined with another targeted therapeutic such as a phosphatidylinositol 3,4,5-trisphosphate (PI3K) inhibitor. To further address the potential mechanisms of resistance to targeted therapies such as PI3K inhibitors, we have generated resistance models under various genetic mutations (PIK3CA and PTEN) in the setting of fulvestrant resistance to ascertain kinases that could potentiate tumor survival. Phosphoproteomic analysis of PTEN deficient tumors resistant to PI3K inhibition identified ATM as a top kinase for further validation as to its role in the development of PI3K resistance. For clinical relevance we are also investigating PIK3CA mutants to determine if results observed from phosphoproteomic analyses in a PTEN-deficient model could be extended to models with other forms of PI3K pathway activation and resistance to other subtypes of PI3K inhibitors. Preliminary work has identified that PI3KCA mutant cell lines resistant to both fulvestrant and GDC-0941 show increased sensitivity to ATM inhibition. These findings promote further investigation as to ATM inhibition’s effects on PTEN deficient lines.
Romo, Bianca A., "Estrogen Receptor (ER) Alpha Regulatory Mechanisms and Therapeutic Strategies in ER+ Breast Cancer" (2024). Dartmouth College Ph.D Dissertations. 182.