Bone morphogenetic proteins in breast cancer: dual role in tumourigenesis? (1)
Bone morphogenetic proteins (BMPs) are extracellular signaling molecules that constitute the largest branch of the transforming growth factor b (TGFb) superfamily. In somatic cancers, several in vitro and in vivo studies have examined BMPs in various cancer types originating from a plethora of different tissues such as breast, prostate, bone, skin, lung, pancreas, colon, intestine, brain and ovaries.
BMPs, some of which are called growth and differentiation factors (GDF), are dimeric molecules composed of two identical monomers linked with a disulfide bond. Currently, there are 21 known members in the human BMP family (BMP2–BMP7, BMP8A/B, BMP10, BMP15, GDF1–3, GDF5–7, myostatin, GDF9–11 and GDF15)
Only Bmp2 and Bmp4 have been proposed to regulate the development of mouse mammary glands.
The ligand binds to two separate transmembrane serine–threonine kinase receptors, type I and type II, forming a heterotetrameric complex. In the complex, type II receptor phosphorylates and activates the type I receptor that in turn is able to phosphorylate and activate cytosolic SMAD proteins. Receptor-regulated SMADs (R-SMADs) form complexes with common SMAD (Co-SMAD), and these active SMAD complexes regulate transcription of target genes in the nucleus. BMP ligands can bind three different type I and three different type II receptors.
Type I receptors include BMP receptor type IA (BMPR1A or ALK-3), BMP receptor type IB (BMPR1B or ALK-6) and activin A receptor type I (ACVR1 or ALK-2). Type II receptors include BMP receptor type II (BMPR2), activin A receptor type IIA (ACVR2A or ActR-II) and activin A receptor type IIB (ACVR2B or ActR-IIB). The ligand specificity is mainly dictated by the type I receptor because it binds to the ligand with higher affinity than the type II receptor. BMP2 tends to bind BMPR1A more than BMPR1B, BMP4 binds both with similar affinity, whereas BMP7 prefers ACVR1 and BMPR1B. BMP7 and BMP6 interact first with the type II receptor and then recruit type I receptors, whereas BMP2 and BMP4 bind first to the type I receptor and then recruit type II receptors.
The major pathway for BMP signals is composed of intracellular SMAD proteins. BMP-specific receptors activate three R-SMADs (SMAD1, SMAD5 and SMAD8). The SMAD complex interacts with specific DNA sequences called Smad-binding element or BMP response elements in the promoters or enhancers of target genes.
Aberrant expression of the different BMP ligands has been detected in breast cancer.
BMP2 is one of the most frequently studied ligands in breast cancer. BMP2 inhibits breast cancer cell proliferation by G1 arrest of breast cancer cells. This growth arrest required both cytoplasmic signal transducers SMAD1 and SMAD4. BMP2 is upregulated in response to vitamin D analogue treatment, which resulted in growth reduction of breast cancer cells. BMP2 overexpressing MCF-7 breast cancer cells form tumours with pronounced vascularisation in a mouse xenograft model.
BMP6 in breast cancer inhibits growth and migration of cancer cells. Combined treatment with BMP6 and oestrogen inhibits growth of MCF-7 breast cancer cells and reduces p38 MAPK activity; however, BMP6 alone did not affect growth of these cells.
BMP7 protein expression in primary tumours is associated with accelerated bone metastasis formation, and BMP7 expression was further shown to be an independent prognostic factor for early bone metastasis. BMP7 was shown to stimulate growth of two breast cancer cell lines and inhibit growth of four cell lines. In addition, exogenous BMP7 significantly increased the migration and invasion of MDA-MB-231 cells in vitro. Endogenous and exogenous BMP7 treatment results in diminished formation and growth of bone metastases. Similarly to BMP6, BMP7 and oestrogen together inhibit MCF-7 prolifer- ation, but BMP7 alone does not alter cell growth.
BMP4 promoted invasive behaviour of mammary epithelial cells, and thus also cancerous cells because it disturbs the formation of the lumen of mammary epithelial cells. BMP4 reduced migration and invasion of breast cancer cells in vitro and suppressed matrix metallopeptidase (MMP-9) expression, thereby inhibiting invasive behaviour. BMP4 treatment decreased growth of nine breast cancer cell lines studied by inducing a G1 arrest. Interestingly, at the same time, BMP4 increases migration and invasion of a subset of these cell lines, demonstrating a truly dualistic function for BMP4 in breast cancer cells.
Contrary to breast cancer, BMP2 is overexpressed in virtually every lung cancer, and BMP7 is downregulated in prostate cancer. Similarly, BMPR1A, BMPR1B and BMPR2 expression has been shown to be lost in advanced prostate cancer, but such a phenomenon has not been observed in breast cancer.