Breast cancer affects 1 in 8 women in Australia. Although recent advances in treatment of primary breast tumours has resulted in a steady decrease in mortality, patients with metastatic breast cancer continue to have a poor prognosis. The current 5-year survival rate is 27%. There is an urgent need to develop effective therapies to manage advanced breast cancer.
Bone morphogenetic protein 4 (BMP4) has been reported to either inhibit or promote metastasis in different cancer settings, with the tumour suppressor gene, SMAD4 acting as a pivotal mediator of canonical BMP4 signalling. When SMAD4 is mutated or lost, as is frequently seen in cancers of the gastrointestinal tract, non-canonical BMP4 signalling can be induced through the cancer-promoting MAPK, NF-κB and PI3K/AKT pathways. We hypothesise that when SMAD4 is functional, BMP4 signals through the canonical pathway to suppress breast cancer metastasis, and when SMAD4 is non-functional, BMP4 induces non-canonical signalling and promotes metastasis.
We have shown that BMP4 inhibits metastasis in a syngeneic mouse mammary cancer model. We are now investigating whether this effect is mediated by SMAD4-dependent canonical signalling. In the highly metastatic human MDA-MB-231-HM breast cancer and mouse 4T1.2 mammary cancer lines, we have overexpressed BMP4 and reduced the expression of SMAD4. In the SMAD4-negative human MDA-MB-468 breast cancer line, we have overexpressed BMP4 and SMAD4. Consequences of the reduction or restoration of SMAD4 on BMP4-mediated regulation of metastasis are being investigated. Signal transducers and targets of canonical and non-canonical BMP4 signalling will be identified using mass spectrometry and RNA-sequencing, which may explain the contradictory effects of BMP4 on cancer progression. This project will consolidate the rationale for developing small molecule activators of BMP4 signalling to treat metastatic breast tumours with SMAD4 expression, and identify tumours with non-canonical signalling pathways that should be inhibited to prevent disease progression.