TY - JOUR
T1 - 14-3-3ζ orchestrates mammary tumor onset and progression via miR-221-mediated cell proliferation
AU - Rehman, Sumaiyah K.
AU - Li, Shau Hsuan
AU - Wyszomierski, Shannon L.
AU - Wang, Qingfei
AU - Li, Ping
AU - Sahin, Ozgur
AU - Xiao, Yi
AU - Zhang, Siyuan
AU - Xiong, Yan
AU - Yang, Jun
AU - Wang, Hai
AU - Guo, Hua
AU - Zhang, Jitao D.
AU - Medina, Daniel
AU - Muller, William J.
AU - Yu, Dihua
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84892744853&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892744853&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-13-2016
DO - 10.1158/0008-5472.CAN-13-2016
M3 - Article
C2 - 24197133
AN - SCOPUS:84892744853
SN - 0008-5472
VL - 74
SP - 363
EP - 373
JO - Cancer research
JF - Cancer research
IS - 1
ER -