Abstract
Abstract The 14-3-3 proteins are a family of evolutionarily conserved proteins ubiquitously expressed in eukaryotic organisms. 14-3-3 proteins interact with and regulate many different target proteins including oncoproteins and tumor suppressors. Previously, we found that 14-3-3ζ was overexpressed in >40% of human breast cancers and associated with poor clinical outcome of patients. We also showed that 14-3-3ζ contributed to the transformation of MCF10A non-transformed human mammary epithelial cells and multiple breast cancer cells in vitro. Here, to assess the oncogenic capacity of 14-3-3ζ in vivo, we generated transgenic mice with HA-tagged 114-3-3ζ overexpressed in the mammary epithelium, driven by either the whey acidic protein promoter (WAP-HA-14-3-3ζ) or the MMTV- LTR promoter (MMTV-HA-14-3-3ζ). Multiparous WAP-HA-14-3-3ζ transgenic mice developed hyperplastic lesions and showed an increased susceptibility to the induction of mammary tumors by the carcinogen, DMBA. Remarkably, MMTV-HA-14-3-3ζ mice developed mammary tumors with a median tumor latency of 662 days without DMBA treatment. WAP-HA-14-3-3ζ and MMTV-HA-14-3-3ζ mice crossed with MMTV-neu transgenic mice (WAP-ζ.neu and and MMTV-ζ.neu) exhibited accelerated neu-mediated mammary tumorigenesis and metastasis. Compared to the mammary tumors of MMTV-neu mice, 14-3-3ζ overexpression in bitransgenic mice tumors further increased cell proliferation, reduced apoptosis and enhanced angiogenesis. These data indicate that 14-3-3ζ overexpression in the mouse mammary gland promotes the development and progression of mammary tumors and that 14-3-3ζ, in cooperation with other oncogenic events, plays a causal role in mammary tumorigenesis and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2386. doi:10.1158/1538-7445.AM2011-2386
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