title: Deletion of atbf1/zfhx3 in mouse prostate causes neoplastic lesions, likely by attenuation of membrane and secretory proteins and multiple signaling pathways.
abstract: The ATBF1/ZFHX3 gene at 16q22 is the second most frequently mutated gene in human prostate cancer and has reduced expression or mislocalization in several types of human tumors. Nonetheless, the hypothesis that ATBF1 has a tumor suppressor function in prostate cancer has not been tested. In this study, we examined the role of ATBF1 in prostatic carcinogenesis by specifically deleting Atbf1 in mouse prostatic epithelial cells. We also examined the effect of Atbf1 deletion on gene expression and signaling pathways in mouse prostates. Histopathologic analyses showed that Atbf1 deficiency caused hyperplasia and mouse prostatic intraepithelial neoplasia (mPIN) primarily in the dorsal prostate but also in other lobes. Hemizygous deletion of Atbf1 also increased the development of hyperplasia and mPIN, indicating a haploinsufficiency of Atbf1. The mPIN lesions expressed luminal cell markers and harbored molecular changes similar to those in human PIN and prostate cancer, including weaker expression of basal cell marker cytokeratin 5 (Ck5), cell adhesion protein E-cadherin, and the smooth muscle layer marker Sma; elevated expression of the oncoproteins phospho-Erk1/2, phospho-Akt and Muc1; and aberrant protein glycosylation. Gene expression profiling revealed a large number of genes that were dysregulated by Atbf1 deletion, particularly those that encode for secretory and cell membrane proteins. The four signaling networks that were most affected by Atbf1 deletion included those centered on Erk1/2 and IGF1, Akt and FSH, NF-κB and progesterone and β-estradiol. These findings provide in vivo evidence that ATBF1 is a tumor suppressor in the prostate, suggest that loss of Atbf1 contributes to tumorigenesis by dysregulating membrane and secretory proteins and multiple signaling pathways, and provide a new animal model for prostate cancer.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA 30322.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA 30322; Department of Pathology, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA 30322.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA 30322.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Xing
authors.affiliation: Department of Pathology, University of Virginia Health System, Charlottesville, VA.
authors.forename: Henry F
authors.initials: HF
authors.lastname: Frierson
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, GA 30322.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, GA 30322.
authors.forename: Tongzhong
authors.initials: T
authors.lastname: Ju
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, GA 30322.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cummings
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA 30322. Electronic address: j.dong@emory.edu.
authors.forename: Jin-Tang
authors.initials: JT
authors.lastname: Dong
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D029584:Prostatic Secretory Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; D008565:Membrane Proteins; D029584:Prostatic Secretory Proteins; C489511:Zfhx3 protein, mouse