@article{f7748bad818b4cfe9d541398fd3471e8,
title = "Activation of canonical BMP4-Smad7 signaling suppresses breast cancer metastasis",
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 to anoikis, thereby reducing the number of circulating tumor cells. Gene silencing of Bmp4 or its downstream mediator Smad7, reversed this phenotype. Administration of recombinant BMP4 markedly reduced spontaneous metastasis to lung and bone. Elevated levels of BMP4 and SMAD7 were prognostic for improved recurrence-free survival and overall survival in patients with breast cancer, indicating the importance of canonical BMP4 signaling in the suppression of metastasis and highlighting new avenues for therapy against metastatic disease.",
author = "Eckhardt, {Bedrich L.} and Yuan Cao and Redfern, {Andrew D.} and Chi, {Lap Hing} and Burrows, {Allan D.} and Suraya Roslan and Sloan, {Erica K.} and Parker, {Belinda S.} and Sherene Loi and Ueno, {Naoto T.} and Lau, {Peter K.H.} and Bruce Latham and Anderson, {Robin L.}",
note = "Funding Information: 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 of Western 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. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = mar,
day = "15",
doi = "10.1158/0008-5472.CAN-19-0743",
language = "English (US)",
volume = "80",
pages = "1304--1315",
journal = "Cancer Research",
issn = "0008-5472",
number = "6",
}