First evidence supporting a potential role for the BMP/SMAD pathway in the progression of oestrogen receptor‐positive breast cancer

Abstract

Oestrogen receptor expression is generally a sign of better tumour differentiation and comparatively good clinical outcome in invasive breast cancer. However, oestrogen receptor-positive, poorly differentiated carcinomas with a poor clinical outcome exist. The underlying genetic mechanisms and the genes involved remain obscure, even though chromosome 7p gains seem to be associated with these uncommon tumours. In this study, we compared two subsets of oestrogen receptor-positive breast cancers, which differed in tumour grade, cytogenetic instability, and tumour proliferation, for their differential gene expression in order to identify proteins involved in the progression of oestrogen receptor-positive breast cancers. We were able to show by means of subtractive suppression hybridization, real-time reverse transcriptase PCR, and tissue microarray analysis that expression of the bone morphogenetic protein receptor IB (BMPR-IB) is a major hallmark of the progression and dedifferentiation of breast cancer. Strong expression of BMPR-IB was associated with high tumour grade, high tumour proliferation, cytogenetic instability, and a poor prognosis in oestrogen receptor-positive carcinomas. Western blot analysis revealed that downstream signalling of this receptor is mainly mediated via phosphorylation of SMAD 1 in oestrogen receptor-positive breast cancer. Even though BMPR-IB was expressed in oestrogen receptor-positive and -negative breast cancers, an impact on tumour grade, proliferation, and cytogenetic instability, as parameters of tumour progression, could only be demonstrated in oestrogen receptor-positive carcinomas. This pro-proliferative effect was complemented by significant anti-apoptotic activity, indicated by XIAP and IAP-2 expression in BMPR-IB-positive carcinomas. These results show that the BMP/SMAD pathway is activated in breast cancer and may contribute to breast cancer progression and dedifferentiation in oestrogen receptor-positive breast cancer. The definition of this pathway characterizes a new potential target in the molecular treatment of invasive breast cancer.

Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway

“…Studies using a variety of tumor systems revealed that BMP signaling produces a complex set of effects in cancer, in which they can be either protumorigenic or antitumorigenic. On the one hand, BMP signaling has been suggested to inhibit tumorigenesis (Howe et al, 2001;Haramis et al, 2004;Piccirillo et al, 2006;Sneddon et al, 2006;Bleuming et al, 2007), whereas emerging evidence has shown that BMPs promote the invasiveness and metastasis of several types of cancers (Helms et al, 2005;Rothhammer et al, 2005;Yang et al, 2005;Bailey et al, 2007). Although these reports showed the expression of components of BMP signaling cascades in tumor tissues or active BMP signaling in cancer cell lines, no evidence for active BMP signaling in tumor cells in bone metastasis tissues has been reported.…”

“…Furthermore, overexpression of BMP antagonist noggin in tumor cells inhibited osteolytic bone metastasis of lung and prostate cancer in mouse models (Feeley et al, 2006a, b). The expression levels of components of the BMP signaling pathways have also been shown to correlate with the degree of breast cancer malignancy (Helms et al, 2005). These results suggest that BMPs promote the progression of cancer metastasis.…”

Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease

“…Moreover, we have previously characterised a subtype of stage I/IIa oestrogen receptor-positive (ER þ ) poorly differentiated breast carcinomas displaying gains of chromosome 7p. These tumours exhibit shorter time to progression compared with other breast cancer phenotypes and high frequency of 8q gains (Rennstam et al, 2003;Korsching et al, 2004;Helms et al, 2005). In addition, a high proliferation rate combined with a low HER2, p53 and EGFR expression and a high degree of cytogenetic instability were found among these tumours.…”

Short SULF1/SULF2 splice variants predominate in mammary tumours with a potential to facilitate receptor tyrosine kinase-mediated cell signalling

“…To determine if SULF variant expression also correlated with some other cell signalling pathways, the immunocytochemical analysis also detected BMP signalling as revealed by downstream p-Smad 1,5,8 activation in both triple positive and triple negative tumours although some previous studies have shown BMP signalling restricted to only triple positive samples (Helms MW et al 2005). The precise function of BMP signalling in breast cancer, however, is still unclear since specific BMP ligands have been shown to promote as well as inhibit cancer cell growth and migration including metastasis (Alarmo EL 2010) although most such studies are restricted to mainly cell line analyses.…”