Overexpression of 14-3-3σ counteracts tumorigenicity by positively regulating p73 in vivo

Geng,Cuizhi; Sang,Meixiang; Yang,Ruiling; Gao,Wei; Zhou,Tao; Wang,Shijie

doi:10.3892/ol.2011.401

November-December 2011 Volume 2 Issue 6

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November-December 2011 Volume 2 Issue 6

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Article

Overexpression of 14-3-3σ counteracts tumorigenicity by positively regulating p73 in vivo

Authors:
- Cuizhi Geng
- Meixiang Sang
- Ruiling Yang
- Wei Gao
- Tao Zhou
- Shijie Wang
View Affiliations / Copyright

Affiliations: Breast Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China, Tumor Research Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
Pages: 1177-1182
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Published online on: August 31, 2011

https://doi.org/10.3892/ol.2011.401
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Abstract

14-3-3σ, one of the 14-3-3 family members, was initially identified as a human mammary epithelium-specific marker 1. The expression of 14-3-3σ is directly regulated by p53. It has been demonstrated that 14-3-3σ stabilizes p53 and enhances its transcriptional activity through the interaction with p53, suggesting that 14-3-3σ has a positive feedback effect on p53. Our previous study showed that 14-3-3σ is a direct transcriptional target of p73 and enhances the p73-mediated transcriptional as well as pro-apoptotic activity in vitro. In the present study, we explored the tumor-suppressive effect of 14-3-3σ by establishing a breast cancer xenograft nude mouse model with an inducible expression of 14-3-3σ or with an inducible expression of p53/p73 plus 14-3-3σ with ADR treatment. Tumor formation was then assayed. Moreover, 66 primary breast cancer specimens and paired tumor-free breast specimens obtained from the female patients were examined. Results showed that the expression of p73 and 14-3-3σ in breast cancer specimens was significantly lower than the tumor-free breast specimens and that 14-3-3σ expression was positively correlated with the expression of p73. Furthermore, overexpression of 14-3-3σ counteracts tumorigenicity by positively regulating p73 in p53-mutated or -deficient cancers in vivo. Therefore, our results may lead to the use of 14-3-3σ in the therapeutic application for the p53-mutated and p73-expressed breast cancer patients.

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1	Mhawech P: 14-3-3 proteins - an update. Cell Res. 15:228–236. 2005. View Article : Google Scholar : PubMed/NCBI
2	Rosenquist M: 14-3-3 proteins in apoptosis. Braz J Med Biol Res. 36:403–408. 2003. View Article : Google Scholar : PubMed/NCBI
3	Fu H, Subramanian RR and Masters SC: 14-3-3 proteins: structure, function, and regulation. Annu Rev Pharmacol Toxicol. 40:617–647. 2000. View Article : Google Scholar
4	Muslin AJ and Xing H: 14-3-3 proteins: regulation of subcellular localization by molecular interference. Cell Signal. 12:703–709. 2000. View Article : Google Scholar : PubMed/NCBI
5	Van Hemert MJ, Steensma HY and van Heusden GP: 14-3-3 proteins: key regulators of cell division, signalling and apoptosis. Bioessays. 23:936–946. 2001.PubMed/NCBI
6	Hermeking H: The 14-3-3 cancer connection. Nature Rev. 3:931–943. 2003.PubMed/NCBI
7	Ferguson AT, Evron E, Umbricht CB, et al: High frequency of hypermethylation at the 14-3-3σ locus leads to gene silencing in breast cancer. Proc Natl Acad Sci USA. 97:6049–6054. 2000.
8	Lodygin D and Hermeking H: The role of epigenetic inactivation of 14-3-3sigma in human cancer. Cell Res. 15:237–246. 2005. View Article : Google Scholar : PubMed/NCBI
9	Iwata N, Yamamoto H, Sasaki S, et al: Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3 sigma gene in human hepatocellular carcinoma. Oncogene. 19:5298–5302. 2000. View Article : Google Scholar : PubMed/NCBI
10	Gasco M, Bell AK, Heath V, et al: Epigenetic inactivation of 14-3-3 sigma in oral carcinoma: association with p16 (INK4a) silencing and human papillomavirus negativity. Cancer Res. 62:2072–2076. 2002.PubMed/NCBI
11	Gasco M, Sullivan A, Repellin C, et al: Coincident inactivation of 14-3-3sigma and p16INK4a is an early event in vulval squamous neoplasia. Oncogene. 21:1876–1881. 2002. View Article : Google Scholar : PubMed/NCBI
12	Suzuki H, Itoh F, Toyota M, Kikuchi T, Kakiuchi H and Imai K: Inactivation of the 14-3-3 sigma gene is associated with 5V CpG island hypermethylation in human cancers. Cancer Res. 60:4353–4357. 2000.PubMed/NCBI
13	Ikeda K and Inoue S: Estrogen receptors and their downstream targets in cancer. Arch Histol Cytol. 67:435–442. 2004. View Article : Google Scholar : PubMed/NCBI
14	Yang H, Zhao R and Lee MH: 14-3-3sigma, a p53 regulator, suppresses tumor growth of nasopharyngeal carcinoma. Mol Cancer Ther. 5:253–260. 2006. View Article : Google Scholar : PubMed/NCBI
15	Hermeking H, Lengauer C, Polyak K, et al: 14-3-3 σ is a p53-regulated inhibitor of G2/M progression. Mol Cell. 1:3–11. 1997.
16	Taylor WR and Stark GR: Regulation of the G2/M transition by p53. Oncogene. 20:1803–1815. 2001. View Article : Google Scholar : PubMed/NCBI
17	Laronga C, Yang HY, Neel C and Lee MH: Association of the cyclin-dependent kinases and 14-3-3sigma negatively regulates cell cycle progression. J Biol Chem. 275:23106–23112. 2000. View Article : Google Scholar : PubMed/NCBI
18	Yang HY, Wen YY, Chen CH, Lozano G and Lee MH: 14-3-3 σ positively regulates p53 and suppresses tumor growth. Mol Cell Biol. 23:7096–7107. 2003.
19	Ikawa Z, Nakagawara A and Ikawa Y: p53 family genes: structural comparison, expression and mutation. Cell Death Differ. 6:1154–1161. 1999. View Article : Google Scholar : PubMed/NCBI
20	Cattoretti G, Rilke F, Andreola S, D’ Amato L and Domenico D: p53 in breast cancer. Int J Cancer. 41:178–183. 1988. View Article : Google Scholar
21	Moll UM, Riou G and Levine AJ: Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. Proc Natl Acad Sci USA. 89:7262–7266. 1992. View Article : Google Scholar : PubMed/NCBI
22	Sang M, Li Y, Ozaki T, et al: p73-dependent induction of 14-3-3 σ increases the chemo-sensitivity of drug-resistant human breast cancers. Biochem Biophys Res Commun. 347:327–333. 2006.PubMed/NCBI
23	Vayssade M, Haddada H, Faridoni-Laurens L, Tourpin S, Valent A, Bénard J and Ahomadegbe JC: p73 functionally replaces p53 in Adriamycin-treated, p53-deficient breast cancer cells. Int J Cancer. 116:860–869. 2005. View Article : Google Scholar : PubMed/NCBI
24	Prasad GL, Valverius EM, McDuffie E and Cooper HL: Complementary DNA cloning of a novel epithelial cell marker protein, Hmel, that may be down-regulated in neoplastic mammary cells. Cell Growth Differ. 3:507–513. 1992.PubMed/NCBI
25	Vercoutter-Edouart AS, Lemoine J, Le Bourhis X, et al: Proteomic analysis reveals that 14-3-3σ is down-regulated in human breast cancer cells. Cancer Res. 61:76–80. 2001.