FOXF2 oppositely regulates stemness in luminal and basal-like breast cancer cells through the Wnt/beta-catenin pathway

Abstract

The stemness of cancer cells contributes to tumorigenesis, the heterogeneity of malignancies, cancer metastasis, and therapeutic resistance. However, the roles and regulatory mechanisms maintaining stemness among breast cancer subtypes remain elusive. Our previous studies have demonstrated that ectopic expression and dynamic alteration of the mesenchymal transcription factor forkhead box F2 (FOXF2) differentially regulates breast cancer progression and metastasis organotropism in a cell subtype-specific manner. Here, we reveal the underlying mechanism by which FOXF2 enhances stemness in luminal breast cancer cells but suppresses that in basal-like breast cancer (BLBC) cells. We show that luminal breast cancer and BLBC cells with FOXF2-regulated stemness exhibit partial mesenchymal stem cell properties that toward osteogenic differentiation and myogenic differentiation, respectively. Furthermore, we show that FOXF2 activates the Wnt signaling pathway in luminal breast cancer cells but represses this pathway in BLBC cells by recruiting nuclear receptor coactivator 3 (NCoA3) and nuclear receptor corepressor 1 (NCoR1) to the promoters of Wnt family member 2B (WNT2B) and frizzled class receptor 1 (FZD1) genes to activate and repress their transcription, respectively. We propose that targeting the Wnt signaling pathway is a promising strategy for the treatment of breast cancers with dysregulated expression of FOXF2. The stemness of cancer cells contributes to tumorigenesis, the heterogeneity of malignancies, cancer metastasis, and therapeutic resistance. However, the roles and regulatory mechanisms maintaining stemness among breast cancer subtypes remain elusive. Our previous studies have demonstrated that ectopic expression and dynamic alteration of the mesenchymal transcription factor forkhead box F2 (FOXF2) differentially regulates breast cancer progression and metastasis organotropism in a cell subtype-specific manner. Here, we reveal the underlying mechanism by which FOXF2 enhances stemness in luminal breast cancer cells but suppresses that in basal-like breast cancer (BLBC) cells. We show that luminal breast cancer and BLBC cells with FOXF2-regulated stemness exhibit partial mesenchymal stem cell properties that toward osteogenic differentiation and myogenic differentiation, respectively. Furthermore, we show that FOXF2 activates the Wnt signaling pathway in luminal breast cancer cells but represses this pathway in BLBC cells by recruiting nuclear receptor coactivator 3 (NCoA3) and nuclear receptor corepressor 1 (NCoR1) to the promoters of Wnt family member 2B (WNT2B) and frizzled class receptor 1 (FZD1) genes to activate and repress their transcription, respectively. We propose that targeting the Wnt signaling pathway is a promising strategy for the treatment of breast cancers with dysregulated expression of FOXF2. Breast cancer is a highly heterogeneous disease that can be classified into several intrinsic subtypes with distinct behavior and clinical implications based on molecular profiles (1Perou C.M. Sorlie T. Eisen M.B. van de Rijn M. Jeffrey S.S. Rees C.A. et al.Molecular portraits of human breast tumours.Nature. 2000; 406: 747-752Crossref PubMed Scopus (12239) Google Scholar, 2Sorlie T. Perou C.M. Tibshirani R. Aas T. Geisler S. Johnsen H. et al.Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 10869-10874Crossref PubMed Scopus (8862) Google Scholar). Breast cancers most commonly metastasize to the bone, lung, and liver. The organ preference of metastasis is different among breast cancer subtypes. Luminal breast cancers are prone to metastasize to bone at advanced stage, while basal-like breast cancers (BLBC)/triple-negative breast cancers (TNBC) tend to develop visceral metastasis at early stage (3Rakha E.A. Chan S. Metastatic triple-negative breast cancer.Clin. Oncol. (R Coll. Radiol.). 2011; 23: 587-600Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 4Rodriguez-Pinilla S.M. Sarrio D. Honrado E. Hardisson D. Calero F. Benitez J. et al.Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas.Clin. Cancer Res. 2006; 12: 1533-1539Crossref PubMed Scopus (304) Google Scholar). Epithelial–mesenchymal transition (EMT) is a crucial cellular process for conferring cell plasticity and enabling the invasion-metastasis cascade. EMT involves multiple transition stages that cause cells to gradually progress from epithelial to completely mesenchymal. Cells in different stages of EMT display differences in differentiation status and metastatic potential (5Pastushenko I. Brisebarre A. Sifrim A. Fioramonti M. Revenco T. Boumahdi S. et al.Identification of the tumour transition states occurring during EMT.Nature. 2018; 556: 463Crossref PubMed Scopus (879) Google Scholar, 6Pastushenko I. Blanpain C. EMT transition states during tumor progression and metastasis.Trends Cell Biology. 2019; 29: 212-226Abstract Full Text Full Text PDF PubMed Scopus (1439) Google Scholar, 7Lu W. Kang Y. Epithelial-mesenchymal plasticity in cancer progression and metastasis.Dev. Cell. 2019; 49: 361-374Abstract Full Text Full Text PDF PubMed Scopus (532) Google Scholar), which is tightly linked with the balance between the maintenance of stemness properties and the regulation of differentiation. Forkhead box F2 (FOXF2), a mesenchymal transcription factor (TF), plays critical roles in the maintenance of tissue homeostasis by promoting the differentiation of mesenchymal cells and controlling the mesenchymal transformation of adjacent epithelial cells (8Aitola M. Carlsson P. Mahlapuu M. Enerback S. Pelto-Huikko M. Forkhead transcription factor FoxF2 is expressed in mesodermal tissues involved in epithelio-mesenchymal interactions.Dev. Dyn. 2000; 218: 136-149Crossref PubMed Scopus (90) Google Scholar). Our previous studies have demonstrated that ectopic expression and dynamic alteration of FOXF2 differentially regulates breast cancer progression and metastasis organotropism in a cell subtype-specific manner. FOXF2 overexpression promotes EMT/epithelial–osteogenic transition (EOT) and bone metastasis by pleiotropically transactivating bone-related genes in luminal breast cancer and BLBC cells (9Wang S. Li G.X. Tan C.C. He R. Kang L.J. Lu J.T. et al.FOXF2 reprograms breast cancer cells into bone metastasis seeds.Nat. Commun. 2019; 10: 2707Crossref PubMed Scopus (38) Google Scholar) but represses EMT/epithelial–myogenic transition (EMyoT) and visceral metastasis by pleiotropically transrepressing genes encoding EMT-inducing TFs (10Wang Q.S. Kong P.Z. Li X.Q. Yang F. Feng Y.M. FOXF2 deficiency promotes epithelial-mesenchymal transition and metastasis of basal-like breast cancer.Breast Cancer Res. 2015; 17: 30Crossref PubMed Scopus (54) Google Scholar, 11Kang L.J. Yu Z.H. Cai J. He R. Lu J.T. Hou C. et al.Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.Faseb J. 2019; 33: 6564-6573Crossref PubMed Scopus (17) Google Scholar, 12Cai J. Tian A.X. Wang Q.S. Kong P.Z. Du X. Li X.Q. et al.FOXF2 suppresses the FOXC2-mediated epithelial-mesenchymal transition and multidrug resistance of basal-like breast cancer.Cancer Lett. 2015; 367: 129-137Crossref PubMed Scopus (67) Google Scholar), TGF-βs, and miRNA182 J.T. Tan C.C. He R. X. Wang Q.S. et al.FOXF2 deficiency the visceral metastasis of basal-like breast cancer by and PubMed Scopus Google Scholar) in BLBC cells. However, the mesenchymal stemness and differentiation of breast cancer cells that have FOXF2-regulated EMT metastasis organotropism in a cell subtype-specific remain to be the nuclear receptor corepressor 1 transrepression of FOXF2 in BLBC cells in previous studies L.J. Yu Z.H. Cai J. He R. Lu J.T. Hou C. et al.Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.Faseb J. 2019; 33: 6564-6573Crossref PubMed Scopus (17) Google Scholar, J.T. Tan C.C. He R. X. Wang Q.S. et al.FOXF2 deficiency the visceral metastasis of basal-like breast cancer by and PubMed Scopus Google Scholar), the mechanism underlying the of FOXF2 in luminal breast cancer cells is The Wnt signaling pathway is for stemness and plasticity maintenance and promotes metastatic in the bone R. A. C. et promotes breast cancer metastatic in the bone of Wnt Commun. 2019; 10: PubMed Scopus Google Scholar, S. H. signaling pathway regulates for breast cancer bone in in cancer Sci. PubMed Scopus Google Scholar, S. P. E. M. P. between cancer metastasis and bone and J. Full Text Full Text PDF PubMed Scopus Google Scholar) and visceral I. A. E. H. et between cancer stem cells and their metastatic 2011; PubMed Scopus Google Scholar, P. C. Perou C.M. S. et metastasis Wnt signaling with cancer cell and epithelial-mesenchymal transition in basal-like breast cancer.Cancer Res. PubMed Scopus Google Scholar, I. I. et from triple-negative breast cancer are by with 2019; Scopus Google Scholar) in luminal breast cancer and BLBC cells. The Wnt signaling pathway the of Wnt to frizzled and to signaling the transcription factor signaling cascade. of Wnt and frizzled linked with cancer stemness and metastasis M. and clinical J. Google Scholar), which are by the regulation of multiple genes by the signaling C. H. et al.Identification of a of the PubMed Scopus Google Scholar), I. A. signaling pathway contributes to in Res. PubMed Scopus Google Scholar) and X. of factor by the Wnt and in Res. 2001; Google Scholar). FOXF2 to of Wnt signaling in mesenchymal cells M. J. H. Wang T. et and by mesenchymal Wnt signaling and promoting 2006; PubMed Scopus Google Scholar, A. F. Carlsson P. in of stem cells and by Wnt Full Text Full Text PDF PubMed Scopus Google Scholar). However, and FOXF2 regulates the signaling pathway in luminal breast cancer and BLBC cells this we the of FOXF2 in mesenchymal stemness and differentiation in luminal breast cancer and BLBC cells the underlying mechanisms by which FOXF2 regulates the Wnt and frizzled receptor of the signaling We the transactivating and of FOXF2 for genes of Wnt and frizzled receptor in luminal breast cancer and BLBC cells and the underlying mechanisms by which FOXF2 nuclear receptor coactivator and nuclear receptor respectively. We the therapeutic of Wnt signaling pathway on breast cancers with FOXF2 the of FOXF2 in the stemness of breast cancer human luminal breast cancer cell and BLBC cell and to FOXF2 and to be in luminal breast cancer cell but in BLBC cell FOXF2 expression in FOXF2 and FOXF2 and FOXF2 expression in cells FOXF2 and The stem cell and but class 1 transcription factor by FOXF2 at the and expression in luminal breast cancer cells and by FOXF2 in BLBC cells and that FOXF2 promotes the stemness of luminal breast cancer cells but suppresses the stemness of BLBC cells. the cancer stem cell phenotype of FOXF2-regulated luminal breast cancer and BLBC the cell and cell by The that FOXF2 the of in and luminal breast cancer cells but that in and BLBC cells and The by in that FOXF2 the of and cells in and that of cells in and that FOXF2 regulates stemness in luminal breast cancer and BLBC subtypes. breast cancer cells with FOXF2-regulated stemness have mesenchymal stem cell cells with FOXF2 expression and cells with FOXF2 their cells toward osteogenic differentiation and differentiation. The that the differentiation toward and by FOXF2 expression in cells and by FOXF2 in cells and is that the and of by cells with FOXF2 expression that by cells with FOXF2 that ectopic overexpression of FOXF2 to in luminal breast cancer and BLBC cells and FOXF2 deficiency in in BLBC we the osteogenic and the of cells by The that FOXF2 expression in and while expression in cells but in cells is with previous that luminal breast cancer and BLBC cells with FOXF2 expression and have a to metastasize to bone (9Wang S. Li G.X. Tan C.C. He R. Kang L.J. Lu J.T. et al.FOXF2 reprograms breast cancer cells into bone metastasis seeds.Nat. Commun. 2019; 10: 2707Crossref PubMed Scopus (38) Google Scholar), while BLBC cells have a phenotype and metastasize to visceral J.T. Tan C.C. He R. X. Wang Q.S. et al.FOXF2 deficiency the visceral metastasis of basal-like breast cancer by and PubMed Scopus Google Scholar). that FOXF2 differentially regulates the transition of luminal breast cancer and BLBC cells into partial mesenchymal cells that toward different differentiation the mechanism by which FOXF2 differentially regulates stemness in luminal breast cancer and BLBC Wnt signaling pathway by FOXF2 in luminal breast cancer and BLBC cells The that FOXF2 Wnt signaling pathway in and luminal breast cancer cells but that in and BLBC cells the nuclear of by expression of FOXF2 in luminal breast cancer cells but by FOXF2 in BLBC cells the mechanism by which FOXF2 regulates the signaling in the of genes encoding Wnt and to and to be genes of FOXF2 and that FOXF2 to the promoters of and the and that FOXF2 the of the and promoters the in luminal breast cancer cells and that in BLBC cells FOXF2 the expression of and their encoding in luminal breast cancer cells and that in BLBC cells and Wnt signaling pathway by FOXF2 in luminal breast cancer cells and by FOXF2 in BLBC cells be the overexpression of and and demonstrated that FOXF2 regulates Wnt signaling pathway regulation of and transcription in luminal breast cancer and BLBC cells. the mechanism by which FOXF2 differentially regulates and transcription in luminal breast cancer and BLBC the expression patterns of and genes in luminal breast cancer and BLBC cells based on the expression which luminal cell and basal-like cell The that expression in luminal breast cancer cells in BLBC cells and that expression in BLBC cells in luminal breast cancer cells The and expression of and in and cell by and expression in and luminal breast cancer cells in and BLBC cells and expression in and cells in and cells that and to the transactivating of FOXF2 in luminal breast cancer cells and the of FOXF2 in BLBC respectively. the of and in FOXF2 differentially and transcription in luminal breast cancer and BLBC and in the breast cancer cell The that FOXF2 to a that to the and promoters in luminal breast cancer cells but in BLBC cells FOXF2 the of and promoters and FOXF2-regulated and transcription and and in luminal breast cancer cells. FOXF2 to the promoters of and in BLBC cells but in luminal breast cancer cells and FOXF2 the of the and promoters in BLBC and FOXF2-regulated and transcription and in BLBC cells and FOXF2 regulates and transcription in luminal breast cancer and BLBC cells by recruiting and respectively. the of the Wnt signaling pathway in FOXF2-regulated stemness in luminal breast cancer and BLBC the Wnt signaling pathway and to the Wnt signaling pathway in the and cells in and treatment the osteogenic differentiation and differentiation of FOXF2-regulated cells. The in with of cells and cells in that the expression of FOXF2 bone metastasis and that treatment bone metastasis of cells The in with of cells and cells in that FOXF2 visceral organ metastasis of cells. treatment visceral organ metastasis of cells and The of and the Wnt signaling pathway in tumor tissues by cells by that targeting the Wnt signaling pathway is a promising strategy for the treatment of breast cancers with expression of FOXF2. this we demonstrated that the ectopic expression of FOXF2 in luminal breast cancer cells and deficiency of FOXF2 expression in BLBC cells to of stemness that by expression of stem cell of and and of tumor We that FOXF2 differentially the transition of luminal breast cancer and BLBC cells into partial mesenchymal cells with osteogenic and myogenic differentiation respectively. is with previous that breast cancer cells with FOXF2 expression osteogenic and have a to metastasize to bone, while BLBC cells to have a myogenic phenotype and metastasize to visceral (9Wang S. Li G.X. Tan C.C. He R. Kang L.J. Lu J.T. et al.FOXF2 reprograms breast cancer cells into bone metastasis seeds.Nat. Commun. 2019; 10: 2707Crossref PubMed Scopus (38) Google Scholar, J.T. Tan C.C. He R. X. Wang Q.S. et al.FOXF2 deficiency the visceral metastasis of basal-like breast cancer by and PubMed Scopus Google Scholar). we reveal the mechanism of FOXF2-regulated metastasis organotropism of breast cancer cells by which FOXF2 differentially regulates the of luminal breast cancer and BLBC cells into partial mesenchymal stem cell properties that toward different of differentiation. The Wnt signaling pathway plays in cell and from promoters and and are and respectively. a is a Wnt and is expressed in multiple human cancer and tissues with M. and clinical J. Google Scholar, M. M. T. M. expression and of a member of the Wnt Google Scholar). the have M. regulation of based on the balance of and J. Oncol. PubMed Scopus Google Scholar). this we the of FOXF2 to the we for the that FOXF2 regulates transcription in luminal breast cancer and BLBC cells. Cell subtype-specific regulation by FOXF2 in to be in cancers and metastasis and by the of the and maintenance of the stemness of T. A. F. C. et of Wnt genes and frizzled 1 and in breast and breast J. Oncol. Google Scholar, Wang D. Y. Wang H. et of is with a and resistance of in cell cell 2019; 10: PubMed Scopus Google Scholar, Yang Li D. Y. et of and are with metastasis, and of the Oncol. Res. 2018; PubMed Scopus Google Scholar, F. P. Lu Y. X. of the transcription factor for maintaining the stemness of cancer stem cells and cancer cells into cancer stem Res. 2019; 10: PubMed Scopus Google Scholar). is a by the F. P. Lu Y. X. of the transcription factor for maintaining the stemness of cancer stem cells and cancer cells into cancer stem Res. 2019; 10: PubMed Scopus Google Scholar) but by tumor S. J. Y. P. M. et expression of and in 2019; PubMed Scopus Google Scholar). this we that FOXF2 a of and regulates transcription in luminal breast cancer and BLBC cells. We the between FOXF2 and expression in breast cancer tissues based on The Cancer in luminal but in and and heterogeneity have in that in luminal M. S. S.M. R. C.C. et heterogeneity and disease states in Commun. 2018; PubMed Scopus Google Scholar, W. et tumour and cell in breast Commun. PubMed Scopus Google Scholar, A. Y. A. F. M. et heterogeneity and in human breast cancer.Cancer Cell. 2018; 33: Full Text Full Text PDF PubMed Scopus Google Scholar), which be the underlying for the between cell and clinical tissues in the FOXF2 and genes on the of multiple The and mechanism of FOXF2 in genes in cells cells and in tumor to be in the Furthermore, we the between expression of in breast cancer tissues and of based on tumor of the tumor of in luminal the tumor of the tumor of in that regulatory and controls the metastasis in luminal breast cancer and respectively. The transactivating of TFs is on and the of Our previous studies have demonstrated that FOXF2 reprograms by pleiotropically transactivating and bone-related genes in breast cancer cells of luminal and basal-like subtypes (9Wang S. Li G.X. Tan C.C. He R. Kang L.J. Lu J.T. et al.FOXF2 reprograms breast cancer cells into bone metastasis seeds.Nat. Commun. 2019; 10: 2707Crossref PubMed Scopus (38) Google Scholar) but represses by pleiotropically transrepressing genes encoding EMT-inducing TFs (10Wang Q.S. Kong P.Z. Li X.Q. Yang F. Feng Y.M. FOXF2 deficiency promotes epithelial-mesenchymal transition and metastasis of basal-like breast cancer.Breast Cancer Res. 2015; 17: 30Crossref PubMed Scopus (54) Google Scholar, 11Kang L.J. Yu Z.H. Cai J. He R. Lu J.T. Hou C. et al.Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.Faseb J. 2019; 33: 6564-6573Crossref PubMed Scopus (17) Google Scholar, 12Cai J. Tian A.X. Wang Q.S. Kong P.Z. Du X. Li X.Q. et al.FOXF2 suppresses the FOXC2-mediated epithelial-mesenchymal transition and multidrug resistance of basal-like breast cancer.Cancer Lett. 2015; 367: 129-137Crossref PubMed Scopus (67) Google Scholar), and miRNA182 J.T. Tan C.C. He R. X. Wang Q.S. et al.FOXF2 deficiency the visceral metastasis of basal-like breast cancer by and PubMed Scopus Google Scholar) in BLBC cells. this we that FOXF2 and in luminal breast cancer cells and that in BLBC cells. FOXF2 a in a BLBC cell subtype-specific which by (10Wang Q.S. Kong P.Z. Li X.Q. Yang F. Feng Y.M. FOXF2 deficiency promotes epithelial-mesenchymal transition and metastasis of basal-like breast cancer.Breast Cancer Res. 2015; 17: 30Crossref PubMed Scopus (54) Google Scholar, 11Kang L.J. Yu Z.H. Cai J. He R. Lu J.T. Hou C. et al.Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.Faseb J. 2019; 33: 6564-6573Crossref PubMed Scopus (17) Google Scholar, 12Cai J. Tian A.X. Wang Q.S. Kong P.Z. Du X. Li X.Q. et al.FOXF2 suppresses the FOXC2-mediated epithelial-mesenchymal transition and multidrug resistance of basal-like breast cancer.Cancer Lett. 2015; 367: 129-137Crossref PubMed Scopus (67) Google Scholar, J.T. Tan C.C. He R. X. Wang Q.S. et al.FOXF2 deficiency the visceral metastasis of basal-like breast cancer by and PubMed Scopus Google Scholar, Q.S. He R. Yang F. Kang L.J. Li X.Q. et al.FOXF2 deficiency basal-like breast cancer cells to by the of signaling Lett. 2018; PubMed Scopus Google Scholar). FOXF2 to a with 3 in BLBC cells but in luminal breast cancer cells L.J. Yu Z.H. Cai J. He R. Lu J.T. Hou C. et al.Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.Faseb J. 2019; 33: 6564-6573Crossref PubMed Scopus (17) Google Scholar). this we that the transrepression of and by FOXF2 in BLBC cells this we for the that FOXF2 a for and in a luminal breast cancer cell subtype-specific manner. FOXF2 to transactivating in breast cancer 1 receptor and a coactivator in receptor is and contributes to resistance in human factor and breast cancer et of the receptor coactivator and in resistance in breast Natl. Cancer PubMed Scopus Google Scholar, Y. et expression resistance by expression in breast cancer.Cancer Lett. PubMed Scopus Google Scholar, P. Wang Feng H. et and of coactivator Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). this we that highly expressed in luminal breast cancer cells in BLBC cells and transactivating on FOXF2 in luminal breast cancer cells but in BLBC cells. We that the of FOXF2 with be by in luminal breast cancer cells but in BLBC cells. is that the signaling pathway plays a crucial in metastasis to bone and visceral in breast cancer cells of luminal and basal-like subtypes R. A. C. et promotes breast cancer metastatic in the bone of Wnt Commun. 2019; 10: PubMed Scopus Google Scholar, S. H. signaling pathway regulates for breast cancer bone in in cancer Sci. PubMed Scopus Google Scholar, S. P. E. M. P. between cancer metastasis and bone and J. Full Text Full Text PDF PubMed Scopus Google Scholar, I. A. E. H. et between cancer stem cells and their metastatic 2011; PubMed Scopus Google Scholar, P. C. Perou C.M. S. et metastasis Wnt signaling with cancer cell and epithelial-mesenchymal transition in basal-like breast cancer.Cancer Res. PubMed Scopus Google Scholar, I. I. et from triple-negative breast cancer are by with 2019; Scopus Google Scholar). the Wnt signaling is with breast cancer metastasis X. H. Li X. M. F. Yu J. et on and bone metastasis of breast cancer by Wnt Cell PubMed Scopus Google Scholar, M. A. C. I. expression in breast cancer with to bone 2018; PubMed Scopus Google Scholar, H. S. The Wnt between breast cancer and bone 2015; PubMed Scopus Google Scholar), is a of the signaling and expression in breast and bone be by of the signaling pathway M. A. C. I. expression in breast cancer with to bone 2018; PubMed Scopus Google Scholar). that the signaling pathway FOXF2 visceral metastasis in BLBC and FOXF2 bone metastasis in luminal breast with previous (9Wang S. Li G.X. Tan C.C. He R. Kang L.J. Lu J.T. et al.FOXF2 reprograms breast cancer cells into bone metastasis seeds.Nat. Commun. 2019; 10: 2707Crossref PubMed Scopus (38) Google Scholar, J.T. Tan C.C. He R. X. Wang Q.S. et al.FOXF2 deficiency the visceral metastasis of basal-like breast cancer by and PubMed Scopus Google Scholar), FOXF2 regulates metastasis organotropism of breast cancer in a cell subtype-specific on the by the and signaling the critical roles of the pathway in stemness and and targeting this pathway have for cancer treatment I. I. et from triple-negative breast cancer are by with 2019; Scopus Google Scholar, et activates expression and in breast cancer the PubMed Scopus Google Scholar, therapeutic in PubMed Scopus Google Scholar, signaling pathway in breast on and Breast Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Y. Wnt signaling implications for in cancer and bone Lett. PubMed Scopus Google Scholar). on the that FOXF2 regulates signaling pathway and stemness in a breast cancer cell we breast cancer cells with pathway We that breast cancer cells with FOXF2-regulated stemness to Wnt signaling pathway this that FOXF2 regulates stemness in luminal breast cancer and BLBC cells the signaling Luminal breast cancer and BLBC cells with FOXF2-regulated stemness exhibit partial mesenchymal stem cell properties that toward osteogenic differentiation and myogenic differentiation, respectively. to the roles of FOXF2 in differentially breast cancer progression and metastasis organotropism in a cell subtype-specific manner. and genes of and and a coactivator and corepressor of FOXF2 the of transactivating and transrepressing on FOXF2 in luminal breast cancer and BLBC respectively. that targeting signaling pathway is a promising strategy for the treatment of breast cancers with dysregulated expression of FOXF2. The human breast cancer cell and from cells from cell by and for Cells in with and cells in with factor and factor in for and Wnt signaling pathway cells in with of osteogenic differentiation, cells into at a of 1 and in with and for with for at and the of a of differentiation, cells in with and for with for at The of cells in a at The of cells in the of cells human FOXF2 targeting distinct of human FOXF2 and by for the of breast cancer cells to FOXF2 FOXF2 that in for The are in human FOXF2 expression human and expression targeting distinct of human FOXF2 and and and and and and the controls into cells to the The of are in transcription, and of expression P.Z. Yang F. Li Li X.Q. Feng Y.M. FOXF2 expression metastasis and for breast cancer with Scopus Google Scholar). The and for and by and are in and Y. Tan Wang Q.S. Li X.Q. Feng Y.M. epithelial-mesenchymal transition of breast cancer cells J. PubMed Scopus Google Scholar). and nuclear the to the and for and nuclear respectively. and their are in Cells and in and with and with at for The of cell the to the a The and in cells with The of the genes to by L.J. Yu Z.H. Cai J. He R. Lu J.T. Hou C. et al.Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.Faseb J. 2019; 33: 6564-6573Crossref PubMed Scopus (17) Google Scholar). (10Wang Q.S. Kong P.Z. Li X.Q. Yang F. Feng Y.M. FOXF2 deficiency promotes epithelial-mesenchymal transition and metastasis of basal-like breast cancer.Breast Cancer Res. 2015; 17: 30Crossref PubMed Scopus (54) Google Scholar). The of to the and their are in of for and are in Cells with with a The of L.J. Yu Z.H. Cai J. He R. Lu J.T. Hou C. et al.Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.Faseb J. 2019; 33: 6564-6573Crossref PubMed Scopus (17) Google Scholar). (10Wang Q.S. Kong P.Z. Li X.Q. Yang F. Feng Y.M. FOXF2 deficiency promotes epithelial-mesenchymal transition and metastasis of basal-like breast cancer.Breast Cancer Res. 2015; 17: 30Crossref PubMed Scopus (54) Google Scholar). the status of the Wnt signaling cells in a with of that of of the and of a and a and to of for the of are in in tumor cells into the of at from to 3 cells at from 1 to 1 cells with in 1 at from to 1 cells with a for from 1 by at the cell 3 cells into the of and 1 cells into the of the the the with a for The tumor and with and by and of tissue of and and in a by the at Cancer and The breast cancer cell expression and into a luminal cell and basal-like cell The expression of and in luminal and basal-like cell expression of luminal tumor tissues and tumor tissues in for of the between The to and to the of the genes on breast cancer The of expression for into and with distinct metastasis by the in at in and the are the to the differences between the and and differences in expression between the luminal and basal-like in to the differences in the of metastasis among different with The this are from the The that have of with the of this by the of Y. 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