PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
BMP4 is a bonafide breast cancer metastasis suppressor
BL Eckhardt 1 , A Redfern 2 , EK Sloan 3 , Y Cao 4 , BS Parker 5 , N Ueno 1 & RL Anderson 6
1Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 2School of Medicine, University of Western Australia, Perth, Australia; 3Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; 4Department of Pathology, The University of Melbourne, Parkville, Australia; 5La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia; 6Olivia Newton-John Cancer Research Institute, Heidelberg, Australia.
Metastasis is the major cause of death in breast cancer patients, largely due to the poor efficacy of existing therapies. Here we report that bone morphogenetic protein-4 (BMP4) blocks metastasis in animal models of breast cancer and predicts improved survival in patients. In preclinical models of spontaneous metastasis, we demonstrate that BMP4 acts as an autocrine mediator to modulate a range of known metastasis regulating genes, including SMAD7, via activation of canonical BMP-SMAD signaling. Restored BMP4 expression in metastatic mammary tumour lines blocks metastasis and increases survival by sensitizing cancer cells to anoikis, thereby reducing the number of circulating tumor cells. Knockdown of its downstream mediator SMAD7, reverses the protection against metastasis afforded by BMP4. Silencing of BMP4 in poorly metastatic lines enhanced their metastatic capacity in mice. Finally, administration of recombinant BMP4 markedly reduces spontaneous metastasis to lung and bone. Collectively, these findings demonstrate that BMP4 can modulate the metastatic potential of breast cancer, without impacting on primary tumor growth. As such, we propose that BMP4 is a bonafide breast cancer metastasis suppressor. A high throughput screen for small molecules that mimic the activity of BMP4 is underway. In a cohort of 535 breast cancer samples, we show that BMP4 and SMAD7 are prognostic for improved recurrence-free survival and overall survival in breast cancer patients, indicating the importance of canonical BMP4 signaling in the suppression of metastasis and highlighting new avenues for therapy against metastatic disease.
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Oncology Abstracts
ISSN 2631-4657 (online)
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