Undergraduate Honors Thesis
Reversal of an Epithelial-to-Mesenchymal Transition Program Reveals Heme Metabolism as an Immune Suppressor in Triple-Negative Breast Cancer Public Deposited
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Triple-negative breast cancer (TNBC) cells often undergo at least partial epithelial-to-mesenchymal transition (EMT), which contributes to the aggressive nature of the disease because EMT alters tumor-cell metabolism and enhances immune suppression. The Richer lab recently identified novel tumor cell metabolizing enzymes that produce immunosuppressive metabolites by reversing an EMT program in mesenchymal-like human TNBC cells via restoration of the microRNA miR-200c, a powerful repressor of EMT. These studies demonstrated that the metabolic enzyme heme oxygenase-1 (HO-1) was upregulated in TNBC, as opposed to more epithelial estrogen receptor-positive (ER+) BCs that often maintain high miR-200c expression. Notably, in autoimmune diseases, bilirubin, a HO-1 metabolite, is known to be immunosuppressive. However, the impact of HO-1 on tumor cell survival and role of bilirubin in the TNBC immune microenvironment is understudied. In human and mouse models of TNBC, inhibition of HO-1 decreased tumor cell growth, suggesting that HO-1 may support TNBC cell survival. To assess the impact of bilirubin on immune cells, macrophages were cultured with conditioned media from aggressive mouse mammary carcinoma cell lines with and without HO-1 inhibition, which was achieved using miR-200c restoration, HO-1 knockdown, or a HO-1 inhibitor (SnMP). In each of these models, HO-1 inhibition in tumor cells supported anti-tumor (M1) macrophage polarization. Interestingly, direct treatment of macrophages with bilirubin increased expression of both anti-tumor (M1) and pro-tumor (M2) macrophage polarization markers. These studies suggest that targeting tumor cell-HO-1 may limit breast cancer cell growth and support anti-tumor macrophage function, which could provide rationale for the utilization of HO-1 inhibitors in the clinic to improve overall outcomes for TNBC patients.
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- 2021-03-30
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- 2021-04-12
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SH_Honor_s_thesis_manuscript.pdf | 2021-04-12 | Public | Download |