Metastatic behavior of human breast carcinomas overexpressing the Bcl-x(L)gene: A role in dormancy and organospecificity

The ability of metastatic cells to survive antiapoptotic signals may contri bute to the organospecific-spread patterns of clinical metastasis and dorma ncy. MDA-MB-435 breast cancer cells (435/Bcl-x(L)), which overexpress the B cl-x(L) gene, were labeled with the luciferase gene and injected orthotopic ally into homozygous athymic Balb/c (nude) mice to study the metastatic beh avior of the breast cancer cells. The overexpression of Hcl-x(L) in tumors increased the overall metastatic burden in mice (bones, liver, kidneys, bra in, lungs, and lymph nodes) in comparison with control tumors (435/Neo.luc) during the same time interval (ANOVA, p = 0.005). The principal difference s after 110 days were found in bones, which had 1.5 x 10(5) +/- 1.2 x 10(5) tumor cell equivalents (p = 0.03), and lymph nodes, which had 7.0 x 10(6) +/- 16.0 x 10(6) tumor cell equivalents (p = 0.08). The analyses of light p roduction by tissues at different times showed that cells from 435/Neo.luc and 435/Bcl-x(L).luc tumors were detectable in several organs by the second day after intramammary fat pad implantation. Although initially arriving a t the target organs in similar numbers, 435/Bcl-x(L) cells developed more m etastases than 435/Neo cells, indicating that the Bcl-x(L) gene might have a role in breast cancer dormancy, promoting survival of cells in metastatic fool. Thus, we suggest that overexpression of Bcl-x(L) could counteract th e proapoptotic signals in the microenvironment and favor the successful dev elopment of metastasis in specific organs.