| First Author | Rehman SK | Year | 2014 |
| Journal | Cancer Res | Volume | 74 |
| Issue | 1 | Pages | 363-373 |
| PubMed ID | 24197133 | Mgi Jnum | J:206747 |
| Mgi Id | MGI:5551935 | Doi | 10.1158/0008-5472.CAN-13-2016 |
| Citation | Rehman SK, et al. (2014) 14-3-3zeta orchestrates mammary tumor onset and progression via miR-221-mediated cell proliferation. Cancer Res 74(1):363-73 |
| abstractText | 14-3-3zeta is overexpressed in more than 40% of breast cancers, but its pathophysiologic relevance to tumorigenesis has not been established. Here, we show that 14-3-3zeta overexpression is sufficient to induce tumorigenesis in a transgenic mouse model of breast cancer. MMTV-LTR promoter-driven HA-14-3-3zeta transgenic mice (MMTV-HA-14-3-3zeta) developed mammary tumors, whereas control mice did not. Whey acidic protein promoter-driven HA-14-3-3zeta transgenic mice (WAP-HA-14-3-3zeta) developed hyperplastic lesions and showed increased susceptibility to carcinogen-induced tumorigenesis. When crossed with MMTV-neu transgenic mice, 14-3-3zeta.neu transgenic mice exhibited accelerated mammary tumorigenesis and metastasis compared with MMTV-neu mice. Mechanistically, 14-3-3zeta overexpression enhanced MAPK/c-Jun signaling, leading to increased miR-221 transcription, which inhibited p27 CDKI translation and, consequently, promoted cell proliferation. Importantly, this 14-3-3zeta-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 14-3-3zeta has a causal role in mammary tumorigenesis and progression, acting through miR-221 in cooperation with known oncogenic events to drive neoplastic cell proliferation. |
