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Cancer Res. 2014 Jan 1;74(1):363-373. doi: 10.1158/0008-5472.CAN-13-2016. Epub 2013 Nov 6.

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

Author information

1
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Cancer Biology Program, University of Texas Graduate School of Biomedical Sciences-Houston, TX 77030, USA.
3
Department of Computational Biology and Bioinformatics, F. Hoffmann-La-Roche AG, 4070 Basel, Switzerland.
4
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
5
Molecular Oncology Group, McGill University Health Center, Montreal, Quebec, H3A 1A1, Canada.
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Contributed equally

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.

PMID:
24197133
PMCID:
PMC3947305
DOI:
10.1158/0008-5472.CAN-13-2016
[Indexed for MEDLINE]
Free PMC Article
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