Journal Article

Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells

Fernandez-Luna, Jose L, Real, Pedro J, Sierra, Angels, de Juan, Ana, Lopez-Vega, Jose M, Segovia, Jose C

2002

Overview

Disruption of apoptosis may allow metastatic cell survival and confer resistance to chemotherapeutic drugs. We have analysed the molecular pathways that activate these survival genes in specific sites of metastasis. Estrogen receptor-negative breast cancer cell line MDA-MB435 and two metastatic sublines derived from lung (435L) and brain (435B) were analysed for the expression of members of the Bcl-2 family of apoptosis regulators. The levels of Bcl-2 were higher in the metastatic sublines than in parental cells, which correlated with the activation of Stat3, but not with the expression and/or activation of known bcl-2 transcription factors (CREB and WT1). In the brain subline, both expression of Bcl-2 and Stat3 activation were induced by epidermal growth factor and abrogated after treatment with kinase inhibitors specific for epidermal growth factor receptor or Jak2. Furthermore, transfection of 435B with a dominant-negative Stat3 markedly reduced the expression of Bcl-2 protein, whereas transient expression of a constitutively active Stat3 increased Bcl-2 in parental 435 cells. In addition, blockade of Stat3 activation by treatment with epidermal growth factor receptor and Jak2 kinase inhibitors or transfection with a dominant negative Stat3, sensitizes 435B cells to chemotherapy-induced apoptosis. Our data suggest that an increased activation of the Stat3-Bcl-2 pathway in estrogen receptor-negative metastatic breast cancer cell lines confer a survival advantage to these cells and contribute to their chemoresistance.

• Publisher: Nature Publishing,Nature Publishing Group
• Subject: Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / Bcl-2 protein / bcl-X Protein / Biological and medical sciences / Brain Neoplasms - secondary / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer / Carcinoma - metabolism / Carcinoma - secondary / Cell physiology / Cell survival / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Cells / Cellular signal transduction / Chemoresistance / Chemotherapy / Cyclic AMP response element-binding protein / Cyclic AMP Response Element-Binding Protein - drug effects / Cyclic AMP Response Element-Binding Protein - genetics / Cyclic AMP Response Element-Binding Protein - metabolism / Development and progression / DNA-Binding Proteins - drug effects / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Drug resistance / Drug therapy / Enzyme Inhibitors - pharmacology / Epidermal growth factor / Estrogen receptors / Estrogens / Female / Fundamental and applied biological sciences. Psychology / Genetic aspects / Genotype & phenotype / Health aspects / Humans / Janus Kinase 2 / Kinases / Lung Neoplasms - secondary / Metastases / Metastasis / Molecular and cellular biology / Molecular genetics / Mutagenesis. Repair / Neoplasm Metastasis / Neoplasms, Hormone-Dependent - drug therapy / Neoplasms, Hormone-Dependent - metabolism / Neoplasms, Hormone-Dependent - pathology / Protein-Tyrosine Kinases - antagonists & inhibitors / Protein-Tyrosine Kinases - drug effects / Protein-Tyrosine Kinases - metabolism / Proteins / Proto-Oncogene Proteins / Proto-Oncogene Proteins c-bcl-2 - drug effects / Proto-Oncogene Proteins c-bcl-2 - metabolism / Receptor, Epidermal Growth Factor - antagonists & inhibitors / Receptor, Epidermal Growth Factor - drug effects / Receptor, Epidermal Growth Factor - metabolism / Receptors, Estrogen - drug effects / Receptors, Estrogen - metabolism / Stat3 protein / STAT3 Transcription Factor / Trans-Activators - drug effects / Trans-Activators - genetics / Trans-Activators - metabolism / Transcription activation / Transcription factors / Transcription, Genetic / Transfection / Tumor cell lines / Tumor Cells, Cultured / Tyrphostins - pharmacology