title: FOXF2 suppresses the FOXC2-mediated epithelial-mesenchymal transition and multidrug resistance of basal-like breast cancer.
abstract: Forkhead box (FOX) F2 and FOXC2 belong to the FOX transcription factor superfamily. FOXC2 is recognized as an inducer of epithelial-mesenchymal transition (EMT), and its overexpression promotes basal-like breast cancer (BLBC) metastasis. Our previous study demonstrated that FOXF2 functions as an EMT suppressor and that FOXF2 deficiency promotes BLBC metastasis. However, the relationship between the opposite EMT-related transcription factors FOXF2 and FOXC2 remains unknown. Here, we found that FOXF2 directly targets FOXC2 to negatively regulate FOXC2 transcription in BLBC cells. Functionally, we observed that FOXC2 mediates the FOXF2-regulated EMT phenotype, aggressive behavior, and multiple chemotherapy drug resistance of BLBC cells. Additionally, we detected a significant negative correlation between the FOXF2 and FOXC2 mRNA levels in triple-negative breast cancer (TNBC) tissues. TNBC patients in the FOXF2high/FOXC2low and FOXF2low/FOXC2high groups exhibited the best and worst disease-free survival (DFS), respectively, whereas the patients in the FOXF2high/FOXC2high and FOXF2low/FOXC2low groups exhibited moderate DFS. In summary, we found that FOXF2 transcriptionally targets FOXC2 and suppresses EMT and multidrug resistance by negatively regulating the transcription of FOXC2 in BLBC cells. The combined expression levels of FOXF2 and FOXC2 mRNA might serve as an effective prognostic indicator and could guide tailored therapy for TNBC or BLBC patients.
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Ai-Xian
authors.initials: AX
authors.lastname: Tian
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China; Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Peng-Zhou
authors.initials: PZ
authors.lastname: Kong
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China; Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China; Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, China. Electronic address: ymfeng@tijmu.edu.cn.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Feng
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D010641:Phenotype; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C486413:FOXF2 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; C082078:mesenchyme fork head 1 protein
keywords: Basal-like breast cancer; Epithelial–mesenchymal transition; FOXC2; FOXF2