Inhibitory effect of BMP-2 on the proliferation of breast cancer cells

Chen,Anan; Wang,Dingding; Liu,Xueting; He,Shuilian; Yu,Zhihong; Wang, Ju

doi:10.3892/mmr.2012.962

Inhibitory effect of BMP-2 on the proliferation of breast cancer cells

Authors:
- Anan Chen
- Dingding Wang
- Xueting Liu
- Shuilian He
- Zhihong Yu
- Ju Wang
View Affiliations

Affiliations: Institute of Bioengineering, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, P.R. China , Department of Biotechnology, Institute of Life Science and Biological Pharmacy, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, Guangdong 510006, P.R. China
Published online on: June 21, 2012 https://doi.org/10.3892/mmr.2012.962
Pages: 615-620

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 proteins (BMPs) are involved in diverse biological processes, including cell proliferation, differentiation and apoptosis. Results from the MTT assay revealed that BMP-2 significantly inhibited the proliferation of MDA-MB‑231 and MCF-7 breast cancer cells. The flow cytometric analysis demonstrated that BMP-2 caused G1 arrest and promoted apoptosis. An increase in p21 and cleaved caspase-3 in the two cell lines was detected by western blot analysis, which may be responsible for the suppression of cancer cell proliferation caused by BMP-2. BMP-2 protected MDA-MB-231 and MCF-7 cells from generating xenograft tumors in nude mice. Thus, BMP-2 may be considered as an inhibitor of breast cancer at the early stages of disease.

View Figures

View References

1	Wozney JM, Rosen V, Celeste AJ, et al: Novel regulators of bone formation: molecular clones and activities. Science. 242:1528–1534. 1988. View Article : Google Scholar : PubMed/NCBI
2	Hogan BL: Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev. 10:1580–1594. 1996. View Article : Google Scholar : PubMed/NCBI
3	Reddi AH: Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotechnol. 16:247–252. 1998. View Article : Google Scholar : PubMed/NCBI
4	Hoodless PA, Haerry T, Abdollah S, et al: MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell. 85:489–500. 1996. View Article : Google Scholar
5	Nohe A, Hassel S, Ehrlich M, et al: The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem. 277:5330–5338. 2002. View Article : Google Scholar : PubMed/NCBI
6	Liu F, Ventura F, Doody J and Massague J: Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol. 15:3479–3486. 1995.PubMed/NCBI
7	Nohno T, Ishikawa T, Saito T, et al: Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors. J Biol Chem. 270:22522–22526. 1995. View Article : Google Scholar : PubMed/NCBI
8	Rosenzweig BL, Imamura T, Okadome T, et al: Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci USA. 92:7632–7636. 1995. View Article : Google Scholar
9	Massague J and Chen YG: Controlling TGF-beta signaling. Genes Dev. 14:627–644. 2000.
10	Attisano L and Wrana JL: Smads as transcriptional co-modulators. Curr Opin Cell Biol. 12:235–243. 2000. View Article : Google Scholar : PubMed/NCBI
11	Kimura N, Matsuo R, Shibuya H, Nakashima K and Taga T: BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem. 275:17647–17652. 2000. View Article : Google Scholar : PubMed/NCBI
12	Lee KS, Hong SH and Bae SC: Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein. Oncogene. 21:7156–7163. 2002. View Article : Google Scholar : PubMed/NCBI
13	Guicheux J, Lemonnier J, Ghayor C, Suzuki A, Palmer G and Caverzasio J: Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation. J Bone Miner Res. 18:2060–2068. 2003. View Article : Google Scholar : PubMed/NCBI
14	Johnsen IK, Kappler R, Auernhammer CJ and Beuschlein F: Bone morphogenetic proteins 2 and 5 are down-regulated in adrenocortical carcinoma and modulate adrenal cell proliferation and steroidogenesis. Cancer Res. 69:5784–5792. 2009. View Article : Google Scholar : PubMed/NCBI
15	Ghosh Choudhury G, Kim YS, Simon M, et al: Bone morphogenetic protein 2 inhibits platelet-derived growth factor-induced c-fos gene transcription and DNA synthesis in mesangial cells. Involvement of mitogen-activated protein kinase. J Biol Chem. 274:10897–10902. 1999.
16	Wong GA, Tang V, El-Sabeawy F and Weiss RH: BMP-2 inhibits proliferation of human aortic smooth muscle cells via p21Cip1/Waf1. Am J Physiol Endocrinol Metab. 284:E972–E979. 2003. View Article : Google Scholar : PubMed/NCBI
17	Reinholz MM, Iturria SJ, Ingle JN and Roche PC: Differential gene expression of TGF-beta family members and osteopontin in breast tumor tissue: analysis by real-time quantitative PCR. Breast Cancer Res Treat. 74:255–269. 2002. View Article : Google Scholar : PubMed/NCBI
18	Alarmo EL and Kallioniemi A: Bone morphogenetic proteins in breast cancer: dual role in tumourigenesis? Endocr Relat Cancer. 17:R123–R139. 2010. View Article : Google Scholar : PubMed/NCBI
19	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
20	Ghosh-Choudhury N, Woodruff K, Qi W, Celeste A, Abboud SL and Ghosh Choudhury G: Bone morphogenetic protein-2 blocks MDA MB 231 human breast cancer cell proliferation by inhibiting cyclin-dependent kinase-mediated retinoblastoma protein phosphorylation. Biochem Biophys Res Commun. 272:705–711. 2000. View Article : Google Scholar
21	Raida M, Clement JH, Ameri K, Han C, Leek RD and Harris AL: Expression of bone morphogenetic protein 2 in breast cancer cells inhibits hypoxic cell death. Int J Oncol. 26:1465–1470. 2005.PubMed/NCBI
22	Steinert S, Kroll TC, Taubert I, et al: Differential expression of cancer-related genes by single and permanent exposure to bone morphogenetic protein 2. J Cancer Res Clin Oncol. 134:1237–1245. 2008. View Article : Google Scholar : PubMed/NCBI
23	Pouliot F, Blais A and Labrie C: Overexpression of a dominant negative type II bone morphogenetic protein receptor inhibits the growth of human breast cancer cells. Cancer Res. 63:277–281. 2003.PubMed/NCBI
24	Alarmo EL, Parssinen J, Ketolainen JM, Savinainen K, Karhu R and Kallioniemi A: BMP7 influences proliferation, migration, and invasion of breast cancer cells. Cancer Lett. 275:35–43. 2009. View Article : Google Scholar : PubMed/NCBI
25	Kim M and Choe S: BMPs and their clinical potentials. BMB Rep. 44:619–634. 2011. View Article : Google Scholar
26	Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ: The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 75:805–816. 1993. View Article : Google Scholar : PubMed/NCBI
27	Fong S, Itahana Y, Sumida T, et al: Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis. Proc Natl Acad Sci USA. 100:13543–13548. 2003. View Article : Google Scholar : PubMed/NCBI
28	Clement JH, Marr N, Meissner A, et al: Bone morphogenetic protein 2 (BMP-2) induces sequential changes of Id gene expression in the breast cancer cell line MCF-7. J Cancer Res Clin Oncol. 126:271–279. 2000. View Article : Google Scholar : PubMed/NCBI