Abstract
Bone morphogenetic protein 9 (BMP9), a member of TGF-β superfamily, is reported to inhibit the growth and migration of prostate cancer, osteosarcoma and triple-negative MDA-MB-231 breast cancer cells. However, little is known about the effect of on the biological behaviors of HER2-positive SK-BR-3 breast cancer cells and the underlying mechanisms. This study aimed to investigate the effects of BMP9 on the proliferation and metastasis of SK-BR-3 cells with BMP9 over-expression or BMP9 down-regulated expression. Results indicated that exogenously expressed BMP9 inhibited the proliferation and metastasis of SK-BR-3 cells while decreased endogenous BMP9 expression in SK-BR-3 cells promoted the proliferation and migration of breast cancer cells in vitro and in vivo. In SK-BR-3 cells with BMP9 over-expression, the phosphorylation of HER2, ERK1/2 and AKT was markedly suppressed and the HER2 expression decreased at both mRNA and protein levels, while opposite results were observed in SK-BR-3 cells with BMP9 knock down. When the phosphorylation of ERK1/2 and PI3K/AKT was inhibited by PD98059 and LY294002, respectively, the decreased proliferation and invasion induced by BMP9 knock down were eliminated. These findings suggest that BMP9 can inhibit the proliferation and metastasis of SK-BR-3 cells via inactivating ERK1/2 and PI3K/AKT signaling pathways. Thus, BMP9 may serve as a useful agent in the treatment of HER-2 positive breast cancer.
Highlights
Breast cancer is one of the most common malignancies and the second leading cause of cancer related deaths in women
RT-PCR and western blot assay showed that recombinant SKBR-3/Bone morphogenetic protein 9 (BMP9) and SK-BR-3/siBMP9 cells were well prepared for the subsequent experiments (Figure 1 D)
Immunohistochemistry (IHC) showed that there was a lower expression of HER2, p-HER2, p-ERK1/2 and p-AKT in SK-BR-3/BMP9 group when compared with SK-BR-3 group; while there was a higher expression of HER2, p-HER2, p-ERK1/ 2 and p-AKT in SK-BR-3/siBMP9 group, when compared with SK-BR-3 group (Figure 5D). These findings suggest that BMP9 suppresses the growth of SK-BR-3 cells and BMP9 inhibits the expression of HER2, ERK1/2, PI3K/AKT in SK-BR-3 cells in vivo
Summary
Breast cancer is one of the most common malignancies and the second leading cause of cancer related deaths in women. It is necessary to explore effective strategies for the treatment of breast cancer [2]. The major signaling pathways activated by HER2 include the MAPK and PI3K/AKT pathways [5,6,7], both of which have been shown to be critical for the growth, migration and survival of HER2-positive breast cancer cells. Trastuzumab, which effectively inhibits the HER2 mediated MAPK and PI3K/AKT pathways, is the first target agent approved for the treatment of HER2 positive breast cancer [8,9,10,11,12]. Many HER2-positive breast cancer patients do not respond to or eventually progress after trastuzumab therapy [1]. It is imperative to explore the mechanisms underlying the resistance of breast cancer and to develop novel strategies for the treatment of breast cancer
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