{"doi":"10.21203/rs.3.rs-390171/v1","title":"ZEB2 Regulates Endocrine Therapy Sensitivity and Metastasis in Luminal A Breast Cancer Through a Non-Canonical Mechanism","abstract":"Abstract Purpose: 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.","journal":"Research Square","year":2021,"id":229552,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":376490,"name":"Margarite D. Matossian","orcid":"0000-0002-9527-1043","position":1,"is_corresponding":false},{"id":801132,"name":"Lyndsay V. Rhodes","orcid":"0000-0001-7672-2059","position":2,"is_corresponding":false},{"id":612314,"name":"Theresa B. Phamduy","orcid":null,"position":3,"is_corresponding":false},{"id":376491,"name":"Steven Elliott","orcid":"0000-0003-1167-867X","position":4,"is_corresponding":false},{"id":377661,"name":"Aaron Buechlein","orcid":null,"position":5,"is_corresponding":false},{"id":4131,"name":"Douglas B. Rusch","orcid":"0000-0002-1066-2687","position":6,"is_corresponding":false},{"id":776631,"name":"David F. Miller","orcid":null,"position":7,"is_corresponding":false},{"id":314340,"name":"Kenneth P. Nephew","orcid":"0000-0003-2192-1346","position":8,"is_corresponding":false},{"id":611918,"name":"Douglas B. Chrisey","orcid":"0000-0001-5969-4770","position":9,"is_corresponding":false},{"id":376498,"name":"Bridgette M. Collins‐Burow","orcid":"0000-0003-0039-6415","position":10,"is_corresponding":false},{"id":376497,"name":"Matthew E. Burow","orcid":"0000-0002-0642-6630","position":11,"is_corresponding":false},{"id":376492,"name":"Hope E. Burks","orcid":"0000-0002-2433-8423","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-18T23:55:01.675482Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}