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

Oncogene volume 21, pages 7611–7618 (2002)Cite this article

Abstract

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.

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Acknowledgements

We thank Richard Jove and James Darnell for providing Stat3 expression vectors, and I Orman for excellent technical assistance. This work was supported by Comision Interministerial de Ciencia y Tecnologia Grant No. SAF99-0139 and by a grant from the ‘Fundacion Marcelino Botin’ (proyecto Terapia Genica) to JL Fernandez-Luna. PJ Real is a recipient of a predoctoral fellowship from the ‘Fundacion Ramon Areces’.

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Authors and Affiliations

  1. Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Santander, 39008, Spain

    Pedro J Real & Jose L Fernandez-Luna

  2. Servicio de Oncologia Medica, Hospital Universitario Marques de Valdecilla, Santander, 39008, Spain

    Ana de Juan & Jose M Lopez-Vega

  3. Centro de Oncologia Molecular, Institut de Recerca Oncologica, Barcelona, 08907, Spain

    Angels Sierra

  4. Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas, Madrid, 28040, Spain

    Jose C Segovia

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  1. Pedro J Real
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Correspondence to Jose L Fernandez-Luna.

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Real, P., Sierra, A., de Juan, A. et al. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene 21, 7611–7618 (2002). https://doi.org/10.1038/sj.onc.1206004

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