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1.
Cell Commun Signal ; 22(1): 248, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38689334

RESUMO

BACKGROUND: Bone morphogenetic protein 4 (BMP4) is a potent inhibitor of breast cancer metastasis. However, a tumor-promoting effect of BMP4 is reported in other tumor types, especially when SMAD4 is inactive. METHODS: To assess the requirement for SMAD4 in BMP4-mediated suppression of metastasis, we knocked down SMAD4 in two different breast tumors and enforced SMAD4 expression in a third line with endogenous SMAD4 deletion. In addition, we assessed the requirement for SMAD4 in tumor cell-specific BMP signalling by expression of a constitutively active BMP receptor. Delineation of genes regulated by BMP4 in the presence or absence of SMAD4 was assessed by RNA sequencing and a BMP4-induced gene, MYO1F was assessed for its role in metastasis. Genes regulated by BMP4 and/or SMAD4 were assessed in a publicly available database of gene expression profiles of breast cancer patients. RESULTS: In the absence of SMAD4, BMP4 promotes primary tumor growth that is accompanied by increased expression of genes associated with DNA replication, cell cycle, and MYC signalling pathways. Despite increased primary tumor growth, BMP4 suppresses metastasis in the absence of tumor cell expression of SMAD4. Consistent with the anti-metastatic activity of BMP4, enforced signalling through the constitutively active receptor in SMAD4 positive tumors that lacked BMP4 expression still suppressed metastasis, but in the absence of SMAD4, the suppression of metastasis was largely prevented. Thus BMP4 is required for suppression of metastasis regardless of tumor SMAD4 status. The BMP4 upregulated gene, MYO1F, was shown to be a potent suppressor of breast cancer metastasis. Gene signature upregulated by BMP4 in the absence of SMAD4 was associated with poor prognosis in breast cancer patients, whereas gene signature upregulated by BMP4 in the presence of SMAD4 was associated with improved prognosis. CONCLUSIONS: BMP4 expression is required for suppression of metastasis regardless of the SMAD4 status of the tumor cells. Since BMP4 is a secreted protein, we conclude that it can act both in an autocrine manner in SMAD4-expressing tumor cells and in a paracrine manner on stromal cells to suppress metastasis. Deletion of SMAD4 from tumor cells does not prevent BMP4 from suppressing metastasis via a paracrine mechanism.


Assuntos
Proteína Morfogenética Óssea 4 , Neoplasias da Mama , Metástase Neoplásica , Transdução de Sinais , Proteína Smad4 , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Humanos , Animais , Feminino , Linhagem Celular Tumoral , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos , Proliferação de Células/genética
2.
Oncogenesis ; 11(1): 38, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35821197

RESUMO

MiR-21 was identified as a gene whose expression correlated with the extent of metastasis of murine mammary tumours. Since miR-21 is recognised as being associated with poor prognosis in cancer, we investigated its contribution to mammary tumour growth and metastasis in tumours with capacity for spontaneous metastasis. Unexpectedly, we found that suppression of miR-21 activity in highly metastatic tumours resulted in regression of primary tumour growth in immunocompetent mice but did not impede growth in immunocompromised mice. Analysis of the immune infiltrate of the primary tumours at the time when the tumours started to regress revealed an influx of both CD4+ and CD8+ activated T cells and a reduction in PD-L1+ infiltrating monocytes, providing an explanation for the observed tumour regression. Loss of anti-tumour immune suppression caused by decreased miR-21 activity was confirmed by transcriptomic analysis of primary tumours. This analysis also revealed reduced expression of genes associated with cell cycle progression upon loss of miR-21 activity. A second activity of miR-21 was the promotion of metastasis as shown by the loss of metastatic capacity of miR-21 knockdown tumours established in immunocompromised mice, despite no impact on primary tumour growth. A proteomic analysis of tumour cells with altered miR-21 activity revealed deregulation of proteins known to be associated with tumour progression. The development of therapies targeting miR-21, possibly via targeted delivery to tumour cells, could be an effective therapy to combat primary tumour growth and suppress the development of metastatic disease.

3.
Drug Discov Today ; 27(1): 257-268, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34469805

RESUMO

The development of novel therapeutics is associated with high rates of attrition, with unexpected adverse events being a major cause of failure. Serious adverse events have led to organ failure, cancer development and deaths that were not expected outcomes in clinical trials. These life-threatening events were not identified during therapeutic development due to the lack of preclinical safety tests that faithfully represented human physiology. We highlight the successful application of several novel technologies, including high-throughput screening, organs-on-chips, microbiome-containing drug-testing platforms and humanised mouse models, for mechanistic studies and prediction of toxicity. We propose the incorporation of similar preclinical tests into future drug development to reduce the likelihood of hazardous therapeutics entering later-stage clinical trials.


Assuntos
Desenvolvimento de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/tendências , Drogas em Investigação/farmacologia , Drogas em Investigação/toxicidade , Ensaios de Triagem em Larga Escala/métodos , Humanos , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/tendências
4.
Cancer Res ; 80(6): 1304-1315, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941699

RESUMO

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.


Assuntos
Proteína Morfogenética Óssea 4/metabolismo , Neoplasias Ósseas/genética , Neoplasias da Mama/patologia , Proteína Smad7/metabolismo , Animais , Comunicação Autócrina , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/uso terapêutico , Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/secundário , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Linhagem Celular Tumoral/transplante , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Intervalo Livre de Doença , Regulação para Baixo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Glândulas Mamárias Animais/patologia , Mastectomia , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica/patologia , Metástase Neoplásica/prevenção & controle , Prognóstico , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/genética , Proteína Smad4/metabolismo , Proteína Smad7/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Growth Factors ; 37(1-2): 12-28, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272247

RESUMO

Breast cancer is the most prevalent type of cancer amongst women worldwide. The mortality rate for patients with early-stage breast cancer has been decreasing, however, the 5-year survival rate for patients with metastatic disease remains poor, currently at 27%. Here, we have reviewed the current understanding of the role of bone morphogenetic protein (BMP) signaling in breast cancer progression, and have highlighted the discordant results that are reported in different studies. We propose that some of these contradictory outcomes may result from signaling through either the canonical or non-canonical pathways in different cell lines and tumors, or from different tumor-stromal interactions that occur in vivo.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias da Mama/genética , Transdução de Sinais , Animais , Proteínas Morfogenéticas Ósseas/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Proteínas Smad/genética , Proteínas Smad/metabolismo
6.
Dis Model Mech ; 11(7)2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29784888

RESUMO

Breast cancer brain metastases remain largely incurable. Although several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immunocompromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. As seen by immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple-negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo, and potent radio-sensitising properties in vitro The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis.This article has an associated First Person interview with Soo-Hyun Kim, joint first author of the paper.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Genes Neoplásicos , Inibidores de Histona Desacetilases/uso terapêutico , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Camundongos , Invasividade Neoplásica , Fenótipo , Tolerância a Radiação/efeitos dos fármacos , Transdução de Sinais/genética
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