Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance

Abstract

Bone morphogenetic proteins (BMPs) belong to the TGF-β super family, and are essential for the regulation of foetal development, tissue differentiation and homeostasis and a multitude of cellular functions. Naturally, this has led to the exploration of aberrance in this highly regulated system as a key factor in tumourigenesis. Originally identified for their role in osteogenesis and bone turnover, attention has been turned to the potential role of BMPs in tumour metastases to, and progression within, the bone niche. This is particularly pertinent to breast cancer, which commonly metastasises to bone, and in which studies have revealed aberrations of both BMP expression and signalling, which correlate clinically with breast cancer progression. Ultimately a BMP profile could provide new prognostic disease markers. As the evidence suggests a role for BMPs in regulating breast tumour cellular function, in particular interactions with tumour stroma and the bone metastatic microenvironment, there may be novel therapeutic potential in targeting BMP signalling in breast cancer. This review provides an update on the current knowledge of BMP abnormalities and their implication in the development and progression of breast cancer, particularly in the disease-specific bone metastasis.

Keywords: bone metastasis and tumour biology; bone morphogenetic protein; breast cancer.

Figure 1

BMP signalling utilises canonical Smad dependant pathways and non-canonical Smad-independent pathways. According to combination and sequence of receptor complex formation or recruitment if the BMP ligand (two tone sphere) binds to a preformed heteromeric receptor complex this results in Smad dependant signalling. The Smad 1/5/8 complex binds to Smad 4 and translocates to the nucleus whereby they interact with transcription factors, or directly binding to DNA to regulate gene transcription. If the BMP binds to a type I receptor and recruits the type 2 receptor to the complex, Smad-independent signalling results. There are multiple levels of regulation, including inhibitory Smads 6 and 7 (I-Smads), pseudoreceptors lacking the serine/threonine kinase domain (BAMBI), ubiquitination and degradation (Smurf/Nedd4/RNF11) and target gene transcription of negative regulators (such as the BMP antagonists) functioning as negative feedback. There are myriad other BMP target genes in breast cancer such as ID1, Snail, Zeb1, p21, PTEN, MMPs and ER that affect cancer cell functions. The figure was made with pathway builder tools from www.proteinlounge.com. A full colour version of the figure is available at http://dx.doi.org/10.1530/ERC-17-0139

Figure 2

BMPs mediate crosstalk between breast cancer cells and microenvironment during disease progression. BMP signalling by tumour-associated stromal cells (or cancer associated fibroblasts) alter the expression of EMT-related genes in breast cancer cells such as ZEB1, with BMP-2 and 4 in particular, promoting the mesenchymal phenotype. Likewise, breast cancer cells secreting BMP-2 and 4 can stimulate fibroblasts to produce chemokines and enzymes (Tenascin W, MMPs) that promote invasion and motility. Breast cancer cells are then able to disseminate to bone via lymphovascular invasion. However, there are BMPs that reduce invasion (BMP-6, BMP-10, BMP-15) and others who have a dual or bidirectional role dependant on cellular context, such as BMP-4. The figure was created using Servier Medical Art tools http://servier.com. A full colour version of the figure is available at http://dx.doi.org/10.1530/ERC-17-0139

Figure 3

It has been demonstrated that BMP-2, -4, -6, -7, and GDF5, are capable of directly inducing angiogenesis in vascular endothelial cells, whilst effect of BMP 9/10 seems more context dependent. BMP-9 has biphasic effects on endothelial cells. High doses can inhibit endothelial proliferation and migration, whereas low doses can have stimulatory effects. Indirectly, BMPs can act on stromal cells to promote the secretion of pro- angiogenic factors such as VEGF. This can be attenuated by BMP antagonism such as Noggin attenuating the pro-angiogenic effect of BMP 7. Another BMP antagonist, gremlin has a BMP independent function promoting angiogenesis by interaction with VEGF receptors. The figure was created using Servier Medical Art tools http://servier.com. A full colour version of the figure is available at http://dx.doi.org/10.1530/ERC-17-0139

Figure 4

BMPs are a vital component of normal bone turnover, stimulating the differentiation of mesenchymal stem cells (MSC) into osteoblasts, which is promoted by oestrogen. Osteoblasts secrete RANKL and OPG. If the balance of RANKL is higher than its inhibitor OPG, RANKL binds to osteoclast precursors and results in their maturation and resultant osteolysis. In the vicious cycle of bone metastases, tumour cells secrete many factors which encourage osteoblast production of RANKL and downregulation of OPG, resulting in net osteolysis, which further releases factors that support the survival and proliferation of the tumour cells. Wnt signalling encourages osteoblast maturation and OPG secretion. DKK1, downstream of BMP signalling, inhibits Wnt signals, and thus tips the balance towards osteolysis and reduced bone mass, making DKK1 a therapeutic target in osteoporosis and osteolytic bone metastases. In the current management of osteolytic bone lesions, denosumab is a RANKL inhibitor, reducing osteoclast maturation and function, whereas bisphosphonates penetrate the bone environment, binding to calcium and are then taken up by osteoclasts resulting in osteoclast apoptosis. The figure was created using Servier Medical Art tools http://servier.com. A full colour version of the figure is available at http://dx.doi.org/10.1530/ERC-17-0139