RESUMO
c-Met is a receptor tyrosine kinase that upon binding of its ligand, hepatocyte growth factor (HGF), activates downstream pathways with diverse cellular functions that are important in organ development and cancer progression. Anomalous c-Met signalling has been described in a variety of cancer types, and the receptor is regarded as a novel therapeutic target. In breast cancer there is a need to develop new treatments, particularly for the aggressive subtypes such as triple-negative and basal-like cancer, which currently lack targeted therapy. Over the last two decades, much has been learnt about the functional role of c-Met signalling in different models of breast development and cancer. This work has been complemented by clinical studies, establishing the prognostic significance of c-Met in tissue samples of breast cancer. While the clinical trials of anti-c-Met therapy in advanced breast cancer progress, there is a need to review the existing evidence so that the potential of these treatments can be better appreciated. The aim of this article is to examine the role of HGF/c-Met signalling in in vitro and in vivo models of breast cancer, to describe the mechanisms of aberrant c-Met signalling in human tissues, and to give a brief overview of the anti-c-Met therapies currently being evaluated in breast cancer patients. We will show that the HGF/c-Met pathway is associated with breast cancer progression and suggest that there is a firm basis for continued development of anti-c-Met treatment, particularly for patients with basal-like and triple-negative breast cancer.
Assuntos
Neoplasias da Mama/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Feminino , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Terapia de Alvo Molecular , Prognóstico , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/química , Proteínas Proto-Oncogênicas c-met/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
BACKGROUND: Basal-like (BL) breast cancer is an aggressive form of breast cancer with limited treatment options. Recent work has identified BL breast cancer as a biologically distinct form of triple-negative breast cancer, with a worse outlook. The receptor tyrosine kinase c-Met is a novel therapeutic target associated with reduced survival in breast cancer. Few studies have specifically addressed the association between c-Met and molecular subtype of breast cancer, yet this is a key consideration when selecting patients for clinical trials. The aim of this study is to evaluate c-Met expression in a large cohort of invasive breast cancers and in particular, its correlation with molecular subtype. METHODS: Immunohistochemistry for c-Met was performed and evaluated on 1274 invasive breast cancers using tissue microarray technology. The c-Met scores were correlated with molecular subtype, survival, and other standard clinicopathological prognostic factors. RESULTS: Multivariate logistic regression showed c-Met was independently associated with BL status (odds ratio=6.44, 95% confidence interval=1.74-23.78, P=.005). There was a positive correlation between c-Met and Her2 (P=.005) and an inverse correlation with tumor size (P<.001). C-Met was an independent poor prognostic factor at Cox regression analysis in all subtypes (hazard ratio=1.85, 95% confidence interval=1.07-3.19, P=.027) and there was a trend toward reduced survival in BL tumors overexpressing c-Met, but this was not significant. CONCLUSIONS: C-Met is independently associated with BL breast cancer. In the future, patients with BL tumors should be included in clinical trials of anti-c-Met therapy.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Adulto , Idoso , Neoplasias da Mama/mortalidade , Estudos de Coortes , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Modelos de Riscos Proporcionais , Receptor ErbB-2/metabolismoRESUMO
BACKGROUND: Breast cancer is a heterogeneous disease that can be classified into one of 4 main molecular sub-types: luminal A, luminal B, Her2 over-expressing and basal-like (BL). These tumour sub-types require different treatments and have different risks of disease progression. BL cancers can be considered a sub-group of Triple negative (TN) cancers since they lack estrogen (ER), progesterone (PR) and Her2 expression. No targeted treatment currently exists for TN/BL cancers. Thus it is important to identify potential therapeutic targets and describe their relationship with established prognostic factors. Focal adhesion kinase (FAK) is upregulated in several human cancers and also plays a functional role in tumour angiogenesis. However, the association between breast cancer sub-types and tumour endothelial-FAK expression is unknown. METHODS: Using immunofluorescence, we quantified FAK expression in tumour endothelial and tumour cell compartments in 149 invasive breast carcinomas and correlated expression with clinical, pathological and molecular parameters. RESULTS: Low endothelial-FAK expression was independently associated with luminal A tumours at univariate (p < 0.001) and multivariate (p = 0.001) analysis. There was a positive correlation between FAK expression in the vascular and tumour cell compartments (Spearman's correlation co-efficient = 0.394, p < 0.001). Additionally, endothelial and tumour cell FAK expression were significantly increased in TN tumours (p = 0.043 and p = 0.033 respectively), in tumours with negative ER and PR status, and in high grade tumours at univariate analysis. CONCLUSION: Our findings establish a relationship between endothelial-FAK expression levels and the molecular sub-type of invasive breast cancer, and suggest that endothelial-FAK expression is potentially more clinically relevant than tumour cell FAK expression in breast cancer.
Assuntos
Biomarcadores Tumorais/biossíntese , Proteína-Tirosina Quinases de Adesão Focal/biossíntese , Invasividade Neoplásica/genética , Neoplasias de Mama Triplo Negativas/genética , Biomarcadores Tumorais/genética , Feminino , Proteína-Tirosina Quinases de Adesão Focal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
A routine mammogram identified changes thought to be due to a lymph node, which was confirmed on biopsy. The lymph node was infiltrated with macrophages and showed fragmented acid-fast bacilli. The patient had been treated for leprosy some years before and was still taking thalidomide for erythema nodosum leprosum. Leprosy-associated lymphadenopathy may be identified on routine breast screening.