Adipsin is an ERα target gene that leads to endocrine resistance in breast cancer with ESR1 mutations

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Issue Date
2020-08
Authors
Malone, Marie Kathryn '20
Degree
MS in Pharmaceutical Sciences
Advisor
Jin, Kideok
Committee Members
Voigt, Jeffrey M.
Dearborn, Richard E.
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Abstract
In ER+ breast cancer, the expression of the estrogen receptor allows for the use of targeted endocrine therapies, however, some populations that undergo this treatment become endocrine resistant and can become metastatic as a result. Of this population, the ERα 1 (ESR1) gene was more frequently mutated than in non-resistant population. The most prevalent mutations, Y537S (YS) and D538G (DG), cause constitutive ER activity that is ligand independent. Adipsin is a complement system component and has been linked to increased proliferation and cancer stem cell-like properties in ER+ breast cancer when secreted by adipocytes. In this study, the cytokine adipsin was found to be upregulated in the secretome of YS and DG mutant MCF7 and T47D cells by human cytokine array analysis. Adipsin mRNA and protein levels were also found to be elevated in these cells by RT-qPCR and ELISA. The complement components C3 and C3aR had increased mRNA levels and C3a had increased protein levels in all ESR1 mutants. Treatment of ESR1 mutants with the C3aR inhibitor SB290157 on cellular viability and cytotoxicity were assessed using a CyQUANT assay and flow cytometry with annexin-V staining. Cellular viability and apoptosis were significantly decreased in all ESR1 mutants compared to WT when treated with SB290157. ESR1 mutant cells were treated with SB290157 and tamoxifen (4-OHT) in combination which revealed an increased sensitivity of these cells to tamoxifen. We have provided evidence that supports the hypothesis that functional inhibition of the Adipsin signaling pathway has the potential to circumvent breast cancer growth and metastasis.
Citation
Malone MK. Adipsin is an ERα target gene that leads to endocrine resistance in breast cancer with ESR1 mutations [thesis]. Ann Arbor (MI): Proquest LLC; 2020. 46 p.
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