Bone morphogenetic protein 6 inhibit stress-induced breast cancer cells apoptosis via both Smad and p38 pathways.

Breast carcinoma is one of the most common malignant tumors and has become a more common cancer in women. BMP6 was abnormally expressed in breast cancer specimens and cell lines. However, the contribution of BMP6 in promoting breast cancer progression remains unknown. The purpose of our study was to establish whether expression of BMP6 in breast cancer cells affect their proliferation or apoptosis and the mechanism. We found that BMP6 inhibited proliferation of MDA-MB-231 cells and blocked cell cycle at G(0)/G(1) stage. BMP6 also inhibited serum deprivation induced apoptosis in MDA-MB-231 cells. At the 4 days of serum starvation, BMP6 reduced the percentage of caspase-3 positive cells from 49% to 21%, BMP6 also reduced sub-G(1) peak induced by serum starvation. In contrast, BMP6 significantly enhanced survivin expression both at mRNA and protein levels. Dominant negative-survivin and Antisense-survivin impaired BMP6 induced antiapoptotic effect. BMP6 enhanced survivin expression at the transcription level in a Smad-dependent manner. BMP6 also played its antiapoptotic effect through activation p38 MAPK signal pathway, independent of smad/survivin pathway. These results suggested that BMP6 induced cell cycle arrest in estrogen-insensitive breast cancer cells. BMP6 inhibits stress-induced apoptosis via both Smad and p38 signal pathways. 2007 Wiley-Liss, Inc.