BMPR-II Mediates Positive Regulation on In Vitro Cell Growth, the Potential Implications for Breast Cancer.

Abstract

Abstract Introduction: Breast cancer is the primary type of female cancer in the UK. We have recently shown that reduced expression of BMPR-IB correlates with poor prognosis, and may be useful as a prognostic indicator in breast cancer (1). This current study aimed to see if a role for the BMP type II receptor (BMPR-II), also exists in the progression of breast cancer.Methods: Expression of BMPR-II was examined in a cohort of 32 normal breast tissue and 112 primary breast tumour tissue samples. Transcript levels of BMPR-II were then determined using quantitative real time-PCR and protein levels were assessed using immunohistochemical (IHC) staining. Finally, ribozyme transgenes were constructed to knock-down BMPR-II expression in MDA-MB-231 cells. The effect this had in vitro cell growth was examined.Results: In normal breast tissue, IHC staining demonstrated strong expression of BMPR-II, specifically in the epithelial cells. In comparison to the normal breast tissue, reduced expression of BMPR-II was evident in the breast tumour samples. BMPR-II transcript levels were further determined using Q-PCR. A trend was evident in that patients with poor prognosis (0.012±0.09) including those with metastasis, local recurrence and breast cancer deaths, demonstrated reduced BMPR-II expression compared to disease free patients (33±13, p=0.09 vs. poor prognosis). Furthermore, lower expression levels were seen in patient samples with a Nottingham Prognosis Index (NPI) greater than 5.4 (poor prognosis group) (18±17) compared to those with NPI <3.4 (good prognosis group) (41±18, p=0.19). Finally, BMPR-II expression was markedly lower in advanced breast cancer of TNM stage 3 and 4 (0±0.1) compared with those of early stage of the disease (TNM1, 46±17, both p<0.01). Despite the clear trend seen, the majority of the data was not found to be significant, suggesting that unlike BMPR-IB, BMPR-II is less useful in predicting prognosis of breast cancer. However, knocking down BMPR-II expression in MDA-MB-231 breast cancer cell line resulted in a reduction of in vitro cell growth, suggesting BMPR-II may play a positive role in breast cancer cell growth. The absorbance of MDA-MB-231BMPR-IIKO cells at day 5 was 1.29±0.09, p<0.01 compared with MDA-MB-231WT (1.90±0.18) and MDA-MB-231GFP control cells (2.30±0.23).Conclusion: This study reveals a trend for BMPR-II in that its expression appears to be reduced in breast cancer patients with poor prognosis. Despite this, it is not as useful of a prognostic indicator as its type I counterpart BMPR-IB, suggesting that in breast cancer progression, BMPR-IB plays a more important role. However, reduced expression of BMPR-II in MDA-MB-231 resulted in a promotion of cell growth, suggesting that BMPs in breast cancer cells may act via BMPR-II to promote tumour growth. However, this needs further investigation.Reference:1. Bokobza SM, et al. Reduced expression of BMPR-IB correlates with poor prognosis and increased proliferation of breast cancer cells. Cancer Genom Proteom, 2009, 6, 101-108 Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3039.