14-3-3ζ orchestrates mammary tumor onset and progression via miR-221-mediated cell proliferation

Sumaiyah K. Rehman, Shau Hsuan Li, Shannon L. Wyszomierski, Qingfei Wang, Ping Li, Ozgur Sahin, Yi Xiao, Siyuan Zhang, Yan Xiong, Jun Yang, Hai Wang, Hua Guo, Jitao D. Zhang, Daniel Medina, William J. Muller, Dihua Yu

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

14-3-3z is overexpressed in more than 40% of breast cancers, but its pathophysiologic relevance to tumorigenesis has not been established. Here, we show that 14-3-3z overexpression is sufficient to induce tumorigenesis in a transgenic mouse model of breast cancer. MMTV-LTR promoter-driven HA-14-3-3z 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.

Original languageEnglish (US)
Pages (from-to)363-373
Number of pages11
JournalCancer research
Volume74
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of '14-3-3ζ orchestrates mammary tumor onset and progression via miR-221-mediated cell proliferation'. Together they form a unique fingerprint.

Cite this