Overexpression of Bcl-xL in human breast cancer cells enhances organ-selective lymph node metastasis.
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 x 10(6) +/- 6 x 10(6) 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- alpha and TGF- beta 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.
España
Laura
L
Centre d'Oncologia Molecular, Institut de Recerca Oncológica, Hospital Duran i Reynals, Ciutat Sanitaria i Universitaria de Bellvitge, Barcelona, Spain.
Fernández
Yolanda
Y
Rubio
Nuria
N
Torregrosa
Angels
A
Blanco
Jeronimo
J
Sierra
Angels
A
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002448:Cell Adhesion; D018450:Disease Progression; D005260:Female; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000096:biosynthesis; D008207:Lymphatic Metastasis / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D008156:Luciferases