KEY TAKEAWAYS
- The study aimed to investigate the contrasting effects of BMP4 on BC metastasis, focusing on the influence of SMAD4 activity.
- The study concluded that BMP4 is essential for suppressing metastasis regardless of tumor cell SMAD4 status, acting via autocrine and paracrine mechanisms.
Bone morphogenetic protein 4 (BMP4) is recognized as a powerful suppressor of breast cancer (BC) metastasis, yet its effects vary in different tumor types, particularly when SMAD4 is inactive.
Lap Hing Chi and the team aimed to elucidate the role of BMP4 in BC metastasis and its relationship with SMAD4 status.
They performed an inclusive analysis to assess the requirement for SMAD4 in BMP4-mediated suppression of metastasis in BC. SMAD4 was knocked down in two different breast tumors, and its expression was enforced in a third line with endogenous SMAD4 deletion. Additionally, the requirement for SMAD4 in tumor cell-specific BMP signaling was evaluated by expressing a constitutively active BMP receptor.
Genes regulated by BMP4 in the presence or absence of SMAD4 were delineated through RNA sequencing, with a focus on the BMP4-induced gene MYO1F and its role in metastasis. Furthermore, genes regulated by BMP4 and/or SMAD4 were examined in a publicly available database of gene expression profiles of patients with BC.
They found that in the absence of SMAD4, BMP4 facilitated primary tumor growth, accompanied by increased expression of genes related to DNA replication, cell cycle, and MYC signaling pathways. Despite this tumor growth, BMP4 effectively suppressed metastasis even without tumor cell expression of SMAD4.
Consistently enforced signaling through a constitutively active receptor in SMAD4-positive tumors lacking BMP4 expression still suppressed metastasis. However, in the absence of SMAD4, this suppression was significantly reduced. Thus, BMP4 is crucial for metastasis suppression regardless of tumor SMAD4 status. The BMP4-upregulated gene, MYO1F, exhibited potent suppression of BC metastasis.
Additionally, the gene signature upregulated by BMP4 in the absence of SMAD4 correlated with poor prognosis in patients with BC, while the signature upregulated by BMP4 in the presence of SMAD4 correlated with improved prognosis.
The study concluded that BMP4 expression is essential for suppressing metastasis regardless of the SMAD4 status of tumor cells. As BMP4 is a secreted protein, it can exert its effects both in an autocrine manner in SMAD4-expressing tumor cells and in a paracrine manner on stromal cells to suppress metastasis. Importantly, the deletion of SMAD4 from tumor cells does not impede BMP4’s ability to suppress metastasis via a paracrine mechanism.
The study was sponsored by the National Health and Medical Research Council of Australia, the Wellcome Trust Pathfinder Award, and the Cancer Council Victoria. RLA was supported by a senior fellowship from NBCF. LHC is supported by a graduate research scholarship from La Trobe University and by a Ronnie Goldberg scholarship. The RNA sequencing analysis was supported by a PhD support scholarship awarded to LHC by Tour de Cure. Olivia Newton-John Cancer Research Institute acknowledges the support of the Operational Infrastructure Program of the Victorian Government.
Source: https://pubmed.ncbi.nlm.nih.gov/38689334/
Chi LH, Redfern AD, Roslan S, et al. (2024). “Loss of tumor-derived SMAD4 enhances primary tumor growth but not metastasis following BMP4 signalling.” Cell Commun Signal. 2024 Apr 30;22(1):248. doi: 10.1186/s12964-024-01559-0. PMID: 38689334; PMCID: PMC11060976.
