◥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.
Identification of brain metastasis genes and therapeutic evaluation of histonewas not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296384 doi: bioRxiv preprint first posted online Apr. 6, 2018; was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296384 doi: bioRxiv preprint first posted online Apr. 6, 2018; 3 SUMMARY STATEMENT 47We introduce a new syngeneic mouse model of spontaneous breast cancer brain metastasis, 48 demonstrate its phenotypic, functional and transcriptomic relevance to human TNBC brain 49 metastasis and test novel therapies. 50 51 All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296384 doi: bioRxiv preprint first posted online Apr. 6, 2018; 4 ABSTRACT 52 Breast cancer brain metastasis remains largely incurable. While several mouse models have 53 been developed to investigate the genes and mechanisms regulating breast cancer brain 54 metastasis, these models often lack clinical relevance since they require the use of immune-55 compromised mice and/or are poorly metastatic to brain from the mammary gland. We 56 describe the development and characterisation of an aggressive brain metastatic variant of the 57 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is 58 selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. 59By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative 60 phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. 61In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate 62 across a brain-derived endothelial monolayer and greater invasive response to brain- was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296384 doi: bioRxiv preprint first posted online Apr. 6, 2018; 5 INTRODUCTION 74Metastasis accounts for the majority of breast cancer-related mortalities and approximately 75 40,000 women were expected to die from the disease in 2017 in the US alone (Ghoncheh et 76 al., 2016). The incidence of brain metastasis in breast cancer patients is estimated at ~30% 77 and is rising, despite more effective systemic therapies (Tabouret et al., 2012). Therapeutic 78 options consist primarily of surgery, whole brain radiation therapy, stereotactic radiosurgery 79 and chemotherapy but these approaches, while extending life, are rarely curative (Eichler et 80 al., 2011). While surgical rese...
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