Journal article

Activation of Canonical BMP4-SMAD7 Signaling Suppresses Breast Cancer Metastasis

Bedrich L Eckhardt, Yuan Cao, Andrew D Redfern, Lap Hing Chi, Allan D Burrows, Suraya Roslan, Erica K Sloan, Belinda S Parker, Sherene Loi, Naoto T Ueno, Peter KH Lau, Bruce Latham, Robin L Anderson

Cancer Research | AMER ASSOC CANCER RESEARCH | Published : 2020

Abstract

Metastasis is the major cause of death in patients with cancer; with no therapeutic cure, treatments remain largely palliative. As such, new targets and therapeutic strategies are urgently required. Here, we show 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, BMP4 acted 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 or therapeutically administered BMP4 protein, blocked metastasis and increased survival by sensitizing cancer cells t..

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Grants

Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by US Army Department of Defense Concept Award


Awarded by Cancer Council Victoria


Awarded by Susan G. Komen for the Cure Fellowship


Awarded by NHMRC


Awarded by NCI


Funding Acknowledgements

We are grateful to Drs. F. Miller, M. Waltham, N. Nakayama, R. Pearson, and P. Humbert for providing cell lines; the Animal Facility and Histology Core (Dr. Sarah Ellis) at Peter MacCallum Cancer Centre (Melbourne, Australia) for technical assistance. We thank Dr. B Haibe-Kains for assistance with R codes, Dr. T. Kogawa for instruction with Rcmdr, Zoe Lai for her aid in animal experiments, and Dr. S. Madden for his analysis of the BreastMark database. We also acknowledge the members of the Anderson and Ueno laboratories for insightful discussion and for critical reading of the manuscript. This project was supported by a National Health and Medical Research Council of Australia (NHMRC) Project Grants (APP400037 and APP1121199 to R.L. Anderson), a Peter MacCallum Cancer Centre Foundation Grant (R.L. Anderson), a US Army Department of Defense Concept Award (BC045396 to R.L. Anderson), Cancer Council Victoria Grant-in-Aid (APP1006425 to R.L. Anderson), a Rare and Aggressive Cancer Research Appropriations State of Texas Grant (N.T. Ueno), an MD Anderson Cancer Centre Seed Funding Grant provided through the Morgan Welch Inflammatory Breast Cancer Research Program (to B.L. Eckhardt), a Susan G. Komen for the Cure Fellowship PDF82506 (to B.L. Eckhardt), and a GlaxoSmithKline post doctorate support grant (to B.L. Eckhardt). E.K. Sloan was supported by an Early Career Fellowship from the National Breast Cancer Foundation of Australia (NBCF), NHMRC 1008865, & NCI CA160890. P.K.H. Lau was supported by the Health Department ofWestern Australia Cancer Research Fellowship. R.L. Anderson was supported by a senior fellowship from NBCF. Olivia Newton-John Cancer Research Institute (Heidelberg, Australia) acknowledges the support of the Operational Infrastructure Program of Victorian Government.