Anti-apoptotic proteins induce non-random genetic alterations that result in selecting breast cancer metastatic cells.
To shed light on the relationships between over-expression of anti-apoptotic proteins, genomic instability, and the metastatic ability of breast cancer cells, we analyzed genetic changes in tumors and metastases by orthotopically injecting MDA-MB 435 cells transfected with anti-apoptotic genes Bcl-xL or Bcl-2 into nude mice. Tumors and metastasis variants were extracted by primary culture from breast, bone, lung, and lymph node from mice with 435/Bcl-xL, 435/Bcl-2, and 435/Neo tumors. Using the Arbitrarily Primed Polymerase Chain Reaction (AP-PCR), which permits the detection of allelic imbalances, we generated four different fingerprints utilizing four primers. We found that the genetic damage fraction (GDF) increased in 435/Bcl-2 (GDF=0.55) and 435/Bcl-xL cells (GDF=0.34), in regard to 435/Neo control cells (GDF=0.29), indicating that non-random genetic alterations occurred in cells secondary to Bcl-2 or Bcl-xL over-expression. Anti-apoptotic proteins render breast cancer cells susceptible to the in vivo acquisition of highly tumorigenic (Kruskal-Wallis, P=0.019) and metastatic (Kruskal-Wallis, P=0.004) activity. We therefore propose that genetic instability is a molecular mechanism favored by anti-apoptotic proteins involved in the selection of highly metastatic cells during tumorigenesis, a pathogenic event favoring the expansion of metastasis.
Méndez
Olga
O
Centre d' Oncologia Molecular, Institut de Recerca Oncológica-IDIBELL, Barcelona, Spain.
Fernández
Yolanda
Y
Peinado
Miguel A
MA
Moreno
Victor
V
Sierra
Angels
A
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016296:Mutagenesis; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D019253:Proto-Oncogene Proteins c-bcl-2