title: 14-3-3ζ orchestrates mammary tumor onset and progression via miR-221-mediated cell proliferation.
abstract: 14-3-3ζ is overexpressed in more than 40% of breast cancers, but its pathophysiologic relevance to tumorigenesis has not been established. Here, we show that 14-3-3ζ overexpression is sufficient to induce tumorigenesis in a transgenic mouse model of breast cancer. MMTV-LTR promoter-driven HA-14-3-3ζ transgenic mice (MMTV-HA-14-3-3ζ) developed mammary tumors, whereas control mice did not. Whey acidic protein promoter-driven HA-14-3-3ζ transgenic mice (WAP-HA-14-3-3ζ) developed hyperplastic lesions and showed increased susceptibility to carcinogen-induced tumorigenesis. When crossed with MMTV-neu transgenic mice, 14-3-3ζ.neu transgenic mice exhibited accelerated mammary tumorigenesis and metastasis compared with MMTV-neu mice. Mechanistically, 14-3-3ζ overexpression enhanced MAPK/c-Jun signaling, leading to increased miR-221 transcription, which inhibited p27 CDKI translation and, consequently, promoted cell proliferation. Importantly, this 14-3-3ζ-miR-221-p27 proliferation axis is also functioning in breast tumors in patients and is associated with high-grade cancers. Taken together, our findings show that overexpression of 14-3-3ζ has a causal role in mammary tumorigenesis and progression, acting through miR-221 in cooperation with known oncogenic events to drive neoplastic cell proliferation.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Cancer Biology Program, University of Texas Graduate School of Biomedical Sciences-Houston, TX 77030, USA.
authors.forename: Sumaiyah K
authors.initials: SK
authors.lastname: Rehman
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shau-Hsuan
authors.initials: SH
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Wyszomierski
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Sahin
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Computational Biology and Bioinformatics, F. Hoffmann-La-Roche AG, 4070 Basel, Switzerland.
authors.forename: Jitao D
authors.initials: JD
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Medina
authors.affiliation: Molecular Oncology Group, McGill University Health Center, Montreal, Quebec, H3A 1A1, Canada.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Cancer Biology Program, University of Texas Graduate School of Biomedical Sciences-Houston, TX 77030, USA.
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation
chemical_list: D048948:14-3-3 Proteins