Osterix transcriptional factor is involved in the metastasis of human breast cancers

Dai,Qiang‑Sheng; Zhou,Hong‑Yan; Wu,Zhuang‑Hong; Long,Jian‑Ting; Shao,Nan; Cheang,Tuck‑Yun; Wang,Shen‑Ming

doi:10.3892/ol.2015.3448

Osterix transcriptional factor is involved in the metastasis of human breast cancers

Authors:
- Qiang‑Sheng Dai
- Hong‑Yan Zhou
- Zhuang‑Hong Wu
- Jian‑Ting Long
- Nan Shao
- Tuck‑Yun Cheang
- Shen‑Ming Wang
View Affiliations

Affiliations: Department of Oncology, First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China, Neurological Intensive Care Unit, First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China, Department of Vascular Surgery, First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China
Published online on: July 1, 2015 https://doi.org/10.3892/ol.2015.3448
Pages: 1870-1874

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The transcriptional factor Osterix is specifically expressed in bone tissues to regulate the differentiation and maturation of osteoblasts. Recent studies have also identified the expression of Osterix in a number of cancer tissues, such as kidney and lung cancers. However, the association of Osterix with the metastasis of breast cancers has never been reported. The present study, for the first time, provides evidence supporting the involvement of Osterix in breast cancer metastasis. Western blotting was employed to investigate the expression of Osterix in a number of human breast cancer cell lines with different metastatic features. Gain‑of‑function and loss‑of‑function experiments were performed in MCF7 cells (low level of metastasis) and MDA‑MB‑361 cells (high level of metastasis). The expression of several metastasis‑associated genes was analyzed by western blotting and quantitative polymerase chain reaction. A firefly luciferase‑based reporter gene assay was conducted in order to study whether Osterix regulated the promoter activities of the MMP2 and MMP9 genes, which play critical roles in cancer metastasis. The results showed that Osterix was highly expressed in the MDA‑MB‑231 and MDA‑MB‑361 cells, but was not detectable in the MCF7 cells. The overexpression of Osterix in the MCF7 cells promoted the expression of VEGF, MMP9 and β‑catenin, while downregulating the expression of E‑cadherin. In addition, suppression of Osterix expression in the MDA‑MB‑361 cells reversed the alteration of VEGF, MMP9, β‑catenin and E‑cadherin expression. A reporter gene assay suggested that Osterix activated MMP2 and MMP9 promoter activity. In conclusion, Osterix is involved in the metastasis of human breast cancer and may be a target for the efficient treatment of human breast cancers.

View Figures

View References

1	Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR and de Crombrugghe B: The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 108:17–29. 2002. View Article : Google Scholar : PubMed/NCBI
2	Matsubara T, Kida K, Yamaguchi A, Hata K, Ichida F, Meguro H, Aburatani H, Nishimura R and Yoneda T: BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. J Biol Chem. 283:29119–29125. 2008. View Article : Google Scholar : PubMed/NCBI
3	Koga T, Matsui Y, Asagiri M, Kodama T, de Crombrugghe B, Nakashima K and Takayanagi H: NFAT and Osterix cooperatively regulate bone formation. Nat Med. 11:880–885. 2005. View Article : Google Scholar : PubMed/NCBI
4	Cao Y, Zhou Z, de Crombrugghe B, Nakashima K, Guan H, Duan X, Jia SF and Kleinerman ES: Osterix, a transcription factor for osteoblast differentiation, mediates antitumor activity in murine osteosarcoma. Cancer Res. 65:1124–1128. 2005. View Article : Google Scholar : PubMed/NCBI
5	Logothetis CJ and Lin SH: Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer. 5:21–28. 2005. View Article : Google Scholar : PubMed/NCBI
6	Steeg PS: Tumor metastasis: Mechanistic insights and clinical challenges. Nat Med. 12:895–904. 2006. View Article : Google Scholar : PubMed/NCBI
7	Schägger H and von Jagow G: Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal Biochem. 166:368–379. 1987. View Article : Google Scholar : PubMed/NCBI
8	Yang D, Guo Q, Guo Y, Peng Y and Ma C: Expression of osterix in metastatic breast cancer cells and its effects on MMP-2, MMP-9 and VEGF promoter activities. Suzhou University Journal of Medical Science. 3:62010.
9	Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI
10	Grigoryan T, Wend P, Klaus A and Birchmeier W: Deciphering the function of canonical Wnt signals in development and disease: Conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes Dev. 22:2308–2341. 2008. View Article : Google Scholar : PubMed/NCBI
11	Ferrara N, Gerber H and LeCouter J: The biology of VEGF and its receptors. Nat Med. 9:669–676. 2003. View Article : Google Scholar : PubMed/NCBI
12	Zebrowski BK, Yano S, Liu W, Shaheen RM, Hicklin DJ, Putnam JB Jr and Ellis LM: Vascular endothelial growth factor levels and induction of permeability in malignant pleural effusions. Clin Cancer Res. 5:3364–3368. 1999.PubMed/NCBI
13	Zebrowski BK, Liu W, Ramirez K, Akagi Y, Mills GB and Ellis LM: Markedly elevated levels of vascular endothelial growth factor in malignant ascites. Ann Surg Oncol. 6:373–378. 1999. View Article : Google Scholar : PubMed/NCBI
14	Berns EM, Klijn JG, Look MP, Grebenchtchikov N, Vossen R, Peters H, Geurts-Moespot A, Portengen H, van Staveren IL, Meijer-van Gelder ME, et al: Combined vascular endothelial growth factor and TP53 status predicts poor response to tamoxifen therapy in estrogen receptor-positive advanced breast cancer. Clin Cancer Res. 9:1253–1258. 2003.PubMed/NCBI
15	Coussens LM, Fingleton B and Matrisian LM: Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science. 295:2387–2392. 2002. View Article : Google Scholar : PubMed/NCBI
16	Curran S and Murray GI: Matrix metalloproteinases: Molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer. 36:1621–1630. 2000. View Article : Google Scholar : PubMed/NCBI
17	Egeblad M and Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2:161–174. 2002. View Article : Google Scholar : PubMed/NCBI
18	Hoekstra R, Eskens FA and Verweij J: Matrix metalloproteinase inhibitors: Current developments and future perspectives. Oncologist. 6:415–427. 2001. View Article : Google Scholar : PubMed/NCBI
19	Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Niwa H, Tsuneyama K and Takano Y: Expressions of MMP-2, MMP-9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma. Anticancer Res. 26:3579–3583. 2006.PubMed/NCBI
20	Sier CF, Kubben FJ, Ganesh S, Heerding MM, Griffioen G, Hanemaaijer R, van Krieken JH, Lamers CB and Verspaget HW: Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma. Brit J Cancer. 74:4131996. View Article : Google Scholar : PubMed/NCBI
21	Liabakk N, Talbot I, Smith RA, Wilkinson K and Balkwill F: Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res. 56:190–196. 1996.PubMed/NCBI