Bone morphogenetic protein 6 inhibit stress‐induced breast cancer cells apoptosis via both smad and P38 pathways

Abstract

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.

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

“…BMP6 neutralization in sera exerted little influence on cell growth (Fig. 9A), implying that BMP6 was not directly involved in regulating cancer cell growth, in agreement with the previous results [49,50]. DFO (at 100 μM) was used as a control to repress cell proliferation (Fig.…”

Bone morphogenic protein 6: a member of a novel class of prognostic factors expressed by normal and malignant plasma cells inhibiting proliferation and angiogenesis

“…This is in agreement with the observation that BMP6 expression develops at the differentiation stage of plasma cells, whereas it is absent in MBCs and only expressed in a small minority of PPC samples. The condition is complicated by the fact that alternative BMP signaling ways through prostanoid generation (Ren et al, 2007) and MAPK (Nohe et al, 2004;Du et al, 2007) have been reported, both pathways being present in MMCs (Hoang et al, 2006;Trojan et al, 2006).…”

“…Phosphorylated SMAD1, -5 or -8 proteins form a complex with SMAD4, the only member of the common-partner SMAD proteins, and translocate to the nucleus, where they interact with other transcription factors (Massague, 2000). Alternate BMP signaling pathways include prostanoid generation through cyclooxygenase-2 (Ren et al, 2007) and MAPK (mitogen-activated protein kinase)-dependant activation of p38 or the Ras-and Erk pathway (Nohe et al, 2004;Du et al, 2007). Both pathways have been reported to be present in MMCs (Hoang et al, 2006;Trojan et al, 2006).…”

Bone morphogenetic proteins in development and progression of breast cancer and therapeutic potential (Review)

“…1A). For example, BMP-2 and BMP-6 inhibit the proliferation of breast cancer cells (2,3). On the other hand, some BMPs may indirectly promote the proliferation of breast cancer cells, such as BMP-4 which has a synergetic effect on the proliferation of breast cancer cells induced by fibroblast growth factor (FGF), epidermal growth factor (EGF) and hepatocyte growth factor (HGF) (4).…”

“…In MDA-MB-468, which only expresses Smad-1, BMP-2 fails to induce p21 and inhibits cellular proliferation (9). BMP-6 inhibits proliferation and induces cell cycle arrest at G0/G1 stage in oestrogeninsensitive breast cancer cells (MDA-MB-231) (2).…”