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Figure summarizing previous work where modulation of epithelial-to-mesenchymal transition (EMT) was used to identify immune modulatory factors that support breast cancer progression.
Identifying Additional Immune Modulators in Breast Cancer
Epithelial-to-mesenchymal transition (EMT) is an essential developmental process that is often co-opted by cancers to facilitate tumor progression and immune suppression. As a postdoctoral fellow, we developed a system to reveal additional immune modulatory factors in aggressive triple-negative breast cancer (TNBC) models by restoring expression of microRNA-200c (miR-200c) to reverse EMT. These studies demonstrated that EMT dramatically alters the cytokine profile of tumors, leading to enhanced M2 macrophage polarization in mesenchymal-like tumors (A). In addition, EMT induced multiple tumor cell metabolizing enzymes (detailed in B and reviewed in C), which produce metabolites with immune suppressive functions. This work led to my interest in the pro-metastatic, immune modulatory enzyme heme oxygenase-1 (HO-1). Research projects in the Williams Lab will build on these works by testing the impact of heme metabolism on anti-tumor immune responses and metabolic rewiring in breast cancer liver metastasis.
Leveraging Translational Research to Identify Vulnerabilities of Metastatic Breast Cancer
Estrogen Receptor-positive (ER+) breast cancers are commonly treated with endocrine therapies such as aromatase inhibitors that decrease circulating estrogen levels. However, in response to AI treatment, ER+ breast cancers often acquire pro-progression mutations in ER (gene ESR1) that predict overall poor prognosis. Utilizing a combination of tissue culture models and clinical breast cancer specimens, we identified pathways enhanced in breast cancers harboring ER mutations compared to those with wildtype ER. This collaborative work revealed an upregulation in androgen receptor expression and immune suppressive pathways (A+B) in tumors with mutant ER. These studies identified novel ESR1 mutant-specific molecular dependencies that when inhibited may prevent progression of therapy resistant, metastatic ER+ breast cancers.
We observed an increased number of immunosuppressive PD-L1 (red) positive macrophages (CD68, green) in metastatic breast cancer specimens with mutant versus wildtype (WT) estrogen receptor (ER).
We developed an proximity ligation assay in human breast cancer cell lines to observe interactions between anti-apoptotic Mcl-1 and pro-apoptotic BIM (red dots). This technique was used throughout these studies to measure the anti-apoptotic activity of Mcl-1.
Cell Death Signaling in Breast Cancer Therapy Resistance
At the start of my graduate school career, little was known about the effect of Mcl-1 (gene MCL1), a cell death inhibitor, on solid tumors. Our work was the first to show that Mcl-1 is an essential resistance mechanism utilized by luminal breast cancers to evade cell death (reviewed in A and studied in B). Endocrine therapies, such as the estrogen receptor downregulator Fulvestrant, also increased Mcl-1 expression (C). Inhibition of Mcl-1 with novel nanoparticles increased cell death in combination with endocrine therapy. We demonstrated that mTOR inhibitors can deplete Mcl-1 expression in luminal breast cancers (D). The overall goal of my work was to improve current and future clinical decisions as Mcl-1 inhibitors, including the one tested in these studies (D), are becoming more widely tested in clinical trials.
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