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Overexpression of Bcl-xL in Human Breast Cancer Cells Enhances Organ-Selective Lymph Node Metastasis

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Abstract

Lymph node metastasis are the first prognostic factor in breast cancer diagnosis and an early event in metastatic spread. To assess the role of anti-apoptotic proteins in lymph node metastatic progression of human breast cancer cells we analyzed the metastatic activity of MDA-MB-435 cells transfected with the Bcl-xL gene, after orthotopic inoculation in Nude Balb/c and in SCID mice. The luciferase gene was introduced by permanent transfection in the 435/Bcl-xL and 435/Neo cells and used as a tumor marker to measure the number of tumor cells lodged in lymph nodes. We found that 435/Bcl-xL tumor cells had enhanced organ-specific metastatic activity, preferentially lodging in peripheral lymph nodes, where at 45 days post-implantation we found 7 × 106± 6× 106 435/Bcl-xL.luc and 2 ±1.1 435/Neo.luc luciferase tagged tumor cell equivalents (TCEs). Metastases were abrogated in mice in which orthotopic tumors were induced with 435/Bcl-xL-antisense cells. Additionally, in vitro experiments show that in 435 cells Bcl-xL-antisense can override the emergence of resistance to apoptosis induced by TNF-α and TGF-β in cells overexpressing Bcl-xL, increasing also adhesion to extracellular matrix proteins. These results point to the relevance of Bcl-xL overexpression inducing lymph node metastasis of breast cancer cells, and to the value of this gene as a target for therapy in order to prevent metastasis.

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Authors and Affiliations

  1. Centre d'Oncologia Molecular, Institut de Recerca Oncológica, Hospital Duran i Reynals, Ciutat Sanitaria i Universitaria de Bellvitge, Spain

    Laura España, Yolanda Fernández, Nuria Rubio, Jeronimo Blanco & Angels Sierra

  2. Facultat de Medicina, Universitat de Barcelona, Spain

    Angels Torregrosa

  3. Consejo Superior de Investigaciones Científicas, Barcelona, Spain

    Jeronimo Blanco

  4. Hosp. Duran i Reynals, C.S.U.B., Gran via s/n, km 2.7, 08907 L' Hospitalet de Llobregat, Barcelona, Spain

    Angels Sierra

Authors
  1. Laura España
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  2. Yolanda Fernández
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  3. Nuria Rubio
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  4. Angels Torregrosa
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  5. Jeronimo Blanco
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  6. Angels Sierra
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España, L., Fernández, Y., Rubio, N. et al. Overexpression of Bcl-xL in Human Breast Cancer Cells Enhances Organ-Selective Lymph Node Metastasis. Breast Cancer Res Treat 87, 33–44 (2004). https://doi.org/10.1023/B:BREA.0000041579.51902.89

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  • DOI: https://doi.org/10.1023/B:BREA.0000041579.51902.89

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