Aberrant promoter DNA methylation inhibits bone morphogenetic protein 2 expression and contributes to drug resistance in breast cancer

Du,Min; Su,Xiao‑Mei; Zhang,Tao; Xing,Yong‑Jun

doi:10.3892/mmr.2014.2276

Aberrant promoter DNA methylation inhibits bone morphogenetic protein 2 expression and contributes to drug resistance in breast cancer

Authors:
- Min Du
- Xiao‑Mei Su
- Tao Zhang
- Yong‑Jun Xing
View Affiliations

Affiliations: Department of Oncology, PLA General Hospital of Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China, Affiliated Stomatological Hospital, PLA General Hospital of Chengdu Military Region, Chengdu, Sichuan 610083, P.R. China
Published online on: May 27, 2014 https://doi.org/10.3892/mmr.2014.2276
Pages: 1051-1055

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

Bone morphogenetic protein 2 (BMP2) is a growth factor that is involved in the development and progression of various types of cancer. However, the epigenetic regulation of the expression of BMP2 and the association between BMP2 expression and drug resistance in breast cancer remains to be elucidated. The present study reported that the expression of BMP2 was significantly decreased in primary breast cancer samples and the MCF‑7/ADR breast cancer mulitdrug resistance cell line, which was closely associated with its promoter DNA methylation status. The expression of BMP2 in MCF‑7/ADR cells markedly increased when treated with 5‑Aza‑2'‑deoxycytidine. Knockdown of BMP2 by specific small interfering RNA enhanced the chemoresistance of the MCF‑7 breast cancer cell line. These findings indicated that epigenetic silencing of BMP2 in breast cancer may be involved in breast cancer progression and drug resistance, and provided a novel prognostic marker and therapeutic strategy for breast cancer.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar
2	Slattery ML, John EM, Torres-Mejia G, et al: Genetic variation in bone morphogenetic proteins and breast cancer risk in hispanic and non-hispanic white women: The breast cancer health disparities study. Int J Cancer. 132:2928–2939. 2013. View Article : Google Scholar
3	Thawani JP, Wang AC, Than KD, et al: Bone morphogenetic proteins and cancer: review of the literature. Neurosurgery. 66:233–246. 2010. View Article : Google Scholar : PubMed/NCBI
4	Buijs JT, Petersen M, van der Horst G, et al: Bone morphogenetic proteins and its receptors; therapeutic targets in cancer progression and bone metastasis? Curr Pharm. 16:1291–1300. 2010. View Article : Google Scholar : PubMed/NCBI
5	Ye S, Park BH, Song KJ, et al: In vivo inhibition of bone morphogenetic protein-2 on breast cancer cell growth. Spine (Phila Pa 1976). 38:E143–E150. 2013. View Article : Google Scholar : PubMed/NCBI
6	Guo D, Huang J and Gong J: Bone morphogenetic protein 4 (BMP4) is required for migration and invasion of breast cancer. Mol Cell Biochem. 363:179–190. 2012. View Article : Google Scholar : PubMed/NCBI
7	Lian WJ, Liu G, Liu YJ, et al: Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer. Oncol Rep. 30:193–200. 2013.PubMed/NCBI
8	Rodriguez-Martinez A, Alarmo EL, Saarinen L, et al: Analysis of BMP4 and BMP7 signaling in breast cancer cells unveils time-dependent transcription patterns and highlights a common synexpression group of genes. BMC Med Genomics. 4:802011. View Article : Google Scholar
9	Wang K, Feng H, Ren W, et al: BMP9 inhibits the proliferation and invasiveness of breast cancer cells MDA-MB-231. J Cancer Res Clin Oncol. 137:1687–1696. 2011. View Article : Google Scholar : PubMed/NCBI
10	Ye L, Bokobza S, Li J, et al: Bone morphogenetic protein-10 (BMP-10) inhibits aggressiveness of breast cancer cells and correlates with poor prognosis in breast cancer. Cancer Sci. 101:2137–2144. 2010. View Article : Google Scholar : PubMed/NCBI
11	You JS and Jones PA: Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell. 22:9–20. 2012. View Article : Google Scholar : PubMed/NCBI
12	Kanwal R and Gupta S: Epigenetic modifications in cancer. Clin Genet. 81:303–311. 2012. View Article : Google Scholar
13	Wen XZ, Akiyama Y, Baylin SB, et al: Frequent epigenetic silencing of the bone morphogenetic protein 2 gene through methylation in gastric carcinomas. Oncogene. 25:2666–2673. 2006. View Article : Google Scholar : PubMed/NCBI
14	Fu B, Wang H, Wang J, et al: Epigenetic regulation of BMP2 by 1,25-dihydroxyvitamin D3 through DNA methylation and histone modification. PLoS One. 8:e614232013. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001.
16	Alarmo EL, Kuukasjärvi T, Karhu R, et al: A comprehensive expression survey of bone morphogenetic proteins in breast cancer highlights the importance of BMP4 and BMP7. Breast Cancer Res Treat. 103:239–246. 2007. View Article : Google Scholar : PubMed/NCBI
17	Davies SR, Watkins G, Douglas-Jones A, et al: Bone morphogenetic proteins 1 to 7 in human breast cancer, expression pattern and clinical/prognostic relevance. J Exp Ther Oncol. 7:327–338. 2008.PubMed/NCBI
18	Ghosh-Choudhury N, Ghosh-Choudhury G, Celeste A, et al: Bone morphogenetic protein-2 induces cyclin kinase inhibitor p21 and hypophosphorylation of retinoblastoma protein in estradiol-treated MCF-7 human breast cancer cells. Biochim Biophys Acta. 1497:186–196. 2000. View Article : Google Scholar
19	Waite KA and Eng C: BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum Mol Genet. 12:679–684. 2003. View Article : Google Scholar : PubMed/NCBI
20	Clement JH, Raida M, Sänger J, et al: Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells. Int J Oncol. 27:401–407. 2005.PubMed/NCBI
21	Raida M, Clement JH, Leek RD, et al: Bone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesis. J Cancer Res Clin Oncol. 131:741–750. 2005. View Article : Google Scholar : PubMed/NCBI
22	Jones PA: Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 13:484–492. 2012. View Article : Google Scholar : PubMed/NCBI
23	De Carvalho DD, Sharma S, You JS, et al: DNA methylation screening identifies driver epigenetic events of cancer cell survival. Cancer Cell. 21:655–667. 2012.PubMed/NCBI
24	Hervouet E, Cartron PF, Jouvenot M, et al: Epigenetic regulation of estrogen signaling in breast cancer. Epigenetics. 8:237–245. 2013. View Article : Google Scholar : PubMed/NCBI
25	Pang JM, Dobrovic A and Fox SB: DNA methylation in ductal carcinoma in situ of the breast. Breast Cancer Res. 15:2062013. View Article : Google Scholar : PubMed/NCBI
26	Connolly R and Stearns V: Epigenetics as a therapeutic target in breast cancer. J Mammary Gland Biol Neoplasia. 17:191–204. 2012. View Article : Google Scholar : PubMed/NCBI
27	Dagdemir A, Durif J, Ngollo M, et al: Breast cancer: mechanisms involved in action of phytoestrogens and epigenetic changes. In Vivo. 27:1–9. 2013.PubMed/NCBI
28	Huang Y, Nayak S, Jankowitz R, et al: Epigenetics in breast cancer: what’s new? Breast Cancer Res. 13:2252011.