title: Zinc Finger Homeodomain Factor Zfhx3 Is Essential for Mammary Lactogenic Differentiation by Maintaining Prolactin Signaling Activity.
abstract: The zinc finger homeobox 3 (ZFHX3, also named ATBF1 for AT motif binding factor 1) is a transcription factor that suppresses prostatic carcinogenesis and induces neuronal differentiation. It also interacts with estrogen receptor α to inhibit cell proliferation and regulate pubertal mammary gland development in mice. In the present study, we examined whether and how Zfhx3 regulates lactogenic differentiation in mouse mammary glands. At different stages of mammary gland development, Zfhx3 protein was expressed at varying levels, with the highest level at lactation. In the HC11 mouse mammary epithelial cell line, an in vitro model of lactogenesis, knockdown of Zfhx3 attenuated prolactin-induced β-casein expression and morphological changes, indicators of lactogenic differentiation. In mouse mammary tissue, knock-out of Zfhx3 interrupted lactogenesis, resulting in underdeveloped glands with much smaller and fewer alveoli, reduced β-casein expression, accumulation of large cytoplasmic lipid droplets in luminal cells after parturition, and failure in lactation. Mechanistically, Zfhx3 maintained the expression of Prlr (prolactin receptor) and Prlr-Jak2-Stat5 signaling activity, whereas knockdown and knock-out of Zfhx3 in HC11 cells and mammary tissues, respectively, decreased Prlr expression, Stat5 phosphorylation, and the expression of Prlr-Jak2-Stat5 target genes. These findings indicate that Zfhx3 plays an essential role in proper lactogenic development in mammary glands, at least in part by maintaining Prlr expression and Prlr-Jak2-Stat5 signaling activity.
authors.affiliation: From the Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: From the Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Gui
authors.initials: G
authors.lastname: Ma
authors.affiliation: From the Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.affiliation: the Ningbo Institute of Medical Sciences, Ningbo 315020, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: From the Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Han
authors.affiliation: From the Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Liya
authors.initials: L
authors.lastname: Fu
authors.affiliation: the Department of Hematology and Medical Oncology, School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322.
authors.forename: Xue-Yuan
authors.initials: XY
authors.lastname: Dong
authors.affiliation: the Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602, and.
authors.forename: Tamas
authors.initials: T
authors.lastname: Nagy
authors.affiliation: From the Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: the Cancer Hospital of Tianjin Medical University, Tianjin 300060, China.
authors.forename: Li
authors.initials: L
authors.lastname: Fu
authors.affiliation: From the Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China,; the Department of Hematology and Medical Oncology, School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322,. Electronic address: j.dong@emory.edu.
authors.forename: Jin-Tang
authors.initials: JT
authors.lastname: Dong
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002364:Caseins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000378:metabolism; D007774:Lactation / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011388:Prolactin / Q000378:metabolism* / Q000494:pharmacology; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002364:Caseins; D018398:Homeodomain Proteins; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; C489511:Zfhx3 protein, mouse; D011388:Prolactin; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2
keywords: STAT5 phosphorylation; ZFHX3/ATBF1; development; homeobox; lactogenic differentiation; mammary gland; peptide hormone; prolactin; prolactin receptor (PRLR); transcription factor