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. SIGNIFICANCE: Targeting the BMP4-SMAD7 signaling axis presents a novel therapeutic strategy to combat metastatic breast cancer, a disease that has had no reduction in patient mortality over 20 years. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/6/1304/F1.large.jpg.
Highlights
Patients with late-stage breast cancer present with tumors that have metastasized to the lung, liver, brain, or bone, eventually compromising organ function and leading to patient death
We first confirmed that Bmp4 transcripts in highly metastatic, weakly metastatic, or nonmetastatic primary tumor epithelial cancer cells decreased with increasing metastatic potential (Fig. 1A)
Immunostaining revealed that bone morphogenetic protein-4 (BMP4) was localized to the epithelial cell compartment in normal mammary glands and in noninvasive orthotopic tumors, but absent from aggressive and metastatic 4T1.2 tumors (Fig. 1C; Supplementary Fig. 1A), indicating that BMP4 levels correlate inversely with metastatic propensity
Summary
Patients with late-stage breast cancer present with tumors that have metastasized to the lung, liver, brain, or bone, eventually compromising organ function and leading to patient death. Impaired BMP signaling through loss of cognate receptor BMP-RII or genetic deletion of canonical BMP-SMAD proteins SMAD1/5, can promote spontaneous metastasis in tumor-prone animal models of breast, prostate, ovarian, and testicular cancer [9,10,11,12,13]. These findings indicate that epithelial tumor cells have an inherent capacity to metastasize and may be influenced by specific modulation of the SMAD pathway.
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