Burks, Hope E.Matossian, Margarite D.Rhodes, Lyndsay VanhoyPhamduy, TheresaElliott, StevenBuechlein, AaronRusch, Douglas B.Miller, David F. B.Nephew, Kenneth P.Chrisey, DouglasCollins-Burow, Bridgette M.Burow, Matthew E.2022-12-272022-12-272021Burks, H. E., Matossian, M. D., Rhodes, L. V., Phamduy, T., Elliott, S., Buechlein, A., Rusch, D. B., Miller, D. F. B., Nephew, K. P., Chrisey, D., Collins-Burow, B. M., & Burow, M. E. (2021). ZEB2 regulates endocrine therapy sensitivity and metastasis in luminal a breast cancer cells through a non-canonical mechanism. Breast Cancer Research and Treatment, 189(1), 25–37. https://doi.org/10.1007/s10549-021-06256-x0167-6806, 1573-7217https://hdl.handle.net/1805/30819PURPOSE: The transcription factors ZEB1 and ZEB2 mediate epithelial-to-mesenchymal transition (EMT) and metastatic progression in numerous malignancies including breast cancer. ZEB1 and ZEB2 drive EMT through transcriptional repression of cell-cell junction proteins and members of the tumor suppressive miR200 family. However, in estrogen receptor positive (ER +) breast cancer, the role of ZEB2 as an independent driver of metastasis has not been fully investigated. METHODS: In the current study, we induced exogenous expression of ZEB2 in ER + MCF-7 and ZR-75-1 breast cancer cell lines and examined EMT gene expression and metastasis using dose-response qRT-PCR, transwell migration assays, proliferation assays with immunofluorescence of Ki-67 staining. We used RNA sequencing to identify pathways and genes affected by ZEB2 overexpression. Finally, we treated ZEB2-overexpressing cells with 17β-estradiol (E2) or ICI 182,780 to evaluate how ZEB2 affects estrogen response. RESULTS: Contrary to expectation, we found that ZEB2 did not increase canonical epithelial nor decrease mesenchymal gene expressions. Furthermore, ZEB2 overexpression did not promote a mesenchymal cell morphology. However, ZEB1 and ZEB2 protein expression induced significant migration of MCF-7 and ZR-75-1 breast cancer cells in vitro and MCF-7 xenograft metastasis in vivo. Transcriptomic (RNA sequencing) pathway analysis revealed alterations in estrogen signaling regulators and pathways, suggesting a role for ZEB2 in endocrine sensitivity in luminal A breast cancer. Expression of ZEB2 was negatively correlated with estrogen receptor complex genes in luminal A patient tumors. Furthermore, treatment with 17β-estradiol (E2) or the estrogen receptor antagonist ICI 182,780 had no effect on growth of ZEB2-overexpressing cells. CONCLUSION: ZEB2 is a multi-functional regulator of drug sensitivity, cell migration, and metastasis in ER + breast cancer and functions through non-canonical mechanisms.en-USPublisher PolicyBreast cancerFemaleGene Expression Regulation, NeoplasticArticle