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Carcinogenesis Advance Access published online on September 3, 2004
Carcinogenesis, doi:10.1093/carcin/bgh272
© 2004 by Oxford University Press
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Received February 3, 2004
Revised August 6, 2004
Accepted August 15, 2004

CANCER BIOLOGY

Organ-selective chemoresistance in metastasis from human breast cancer cells: inhibition of apoptosis, genetic variability and microenvironment at the metastatic focus

Bin Gu 1, Laura España 1, Olga Méndez 1, Angels Torregrosa 2, and Angels Sierra 1*

1 Centre d'Oncologia Molecular, Institut de Recerca Oncológica, Hospital Duran i Reynals, Ciutat Sanitaria i Universitaria de Bellvitge, Barcelona, Spain
2 Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain

* To whom correspondence should be addressed. E-mail: asierra{at}iro.es.


  Abstract

We hypothesized that the development of the most resistant cells during metastasis is favored by anti-apoptotic proteins, leading to the acquisition of an adaptive phenotype crucial to drug resistance at the metastatic foci. In order to test it, we induced metastasis in nude mice, injecting orthotopicaly 435/Bcl-xL or 435/Neo cells, previously transfected with the luciferase gene to use it as a tumor marker, and treated them with a therapeutic doses of docetaxel. We monitored metastasis in mice by calculating tumor cell equivalents (TCEs) present in tissues. Between docetaxel treated and non-treated 435/Bcl-xL.luc mice significant differences in the metastatic burden of lymph nodes (p=0.02) and viscera (p=0.02) were observed. However, treatment did not significantly decrease metastatic burden in bones (p=0.19). Additionally, we analyzed the clonality of metastasis from lung, bone, and lymph node by genomic DNA fingerprinting. Bcl-xL enhanced cell genetic instability in terms of gain and loss fractions (GF=0,18 and LF=-0,21) when compared to the control 435/Neo (GF=0,15 and LF=-0,14). Thus, genetic instability might be a molecular mechanism favored by Bcl-xL evolved in the selection process of breast cancer progression, which results in different genetic changes among metastases from lung, bone, or lymph node, favoring organ-selective chemoresistance.

Keywords: Apoptosis; Bcl-2; Bcl-xL; Breast Cancer; Docetaxel; Genetic Instability; Metastasis.
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