PubMed · 14384613
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
J JPP DA COSTA. 1955. [Breast bleeding].. https://pubmed.ncbi.nlm.nih.gov/14384613/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
LAF-4, which encodes a nuclear protein with transactivation potential, is fused to the MLL gene in acute lymphoblastic leukemia (ALL). We identified LAF-4 as a gene that is transcriptionally deregulated in breast tumors and thus may have a pathological role in mammary tumorigenesis. In line with the previous finding that LAF-4 expression is tissue specific, we did not detect any LAF-4 mRNA in normal mammary epithelial cell lines. However, 2 of 5 breast cancer cell lines were found to express LAF-4 at both the RNA and protein levels. In 2 of 9 primary tumor-normal pairs, the expression of LAF-4 was clearly elevated in the tumor tissue. Using RNA in situ hybridization, we demonstrated that LAF-4 is expressed in mammary tumor cells but not in normal acini. In a group of 64 primary human breast tumors, we found that LAF-4 was overexpressed in approximately 20% of the cases. Although epigenetic changes may be involved in altered expression of some genes, differences in LAF-4 expression were not associated with DNA methylation of the predicted promoter region. Our results suggest that LAF-4 may be a proto-oncogene that is transcriptionally activated in some cases of breast cancer.
We have used cultured human mammary epithelial cells (HMEC) and breast tumor-derived lines to gain information on defects that occur during breast cancer progression. HMEC immortalized by a variety of agents (the chemical carcinogen benzo(a)pyrene, oncogenes c-myc and ZNF217, and/or dominant negative p53 genetic suppressor element GSE22) displayed marked upregulation (10-15 fold) of the telomere-binding protein, TRF2. Upregulation of TRF2 protein was apparently due to differences in post-transcriptional regulation, as mRNA levels remained comparable in finite lifespan and immortal HMEC. TRF2 protein was not upregulated by the oncogenic agents alone in the absence of immortalization, nor by expression of exogenously introduced hTERT genes. We found TRF2 levels to be at least twofold higher than in control cells in 11/15 breast tumor cell lines, suggesting that elevated TRF2 levels are a frequent occurrence during the transformation of breast tumor cells in vivo. The dispersed distribution of TRF2 throughout the nuclei in some immortalized and tumor-derived cells indicated that not all the TRF2 was associated with telomeres in these cells. The process responsible for accumulation of TRF2 in immortalized HMEC and breast tumor-derived cell lines may promote tumorigenesis by contributing to the cells' ability to maintain an indefinite lifespan.
In nontumorigenic mammary epithelial cells (EpH4), transforming growth factor-beta (TGFbeta1) causes cell cycle arrest/apoptosis, but induces epitheliomesenchymal transition (EMT) in Ha-Ras-transformed EpH4 cells (EpRas). EMT is closely correlated with late-stage tumor progression and results in fibroblastic, migratory cells displaying a mesenchymal gene expression program (FibRas). EpRas and FibRas cells showed strongly increased cell substrate adhesion to fibronectin, collagens I/IV and laminin 1. Furthermore, Ras transformation caused enhanced or de-novo expression of the integrin subunits beta1, alpha2 and alpha3, or alpha5 and alpha6, respectively, the latter subunits being even more strongly expressed in FibRas cells. Importantly, polarized EpRas cells expressed integrin subunits beta1 and alpha6 at distinct (apical and lateral) membrane domains, while FibRas cells coexpressed these integrins and alpha5 at the entire plasma membrane. During EMT, EpRas cells formed an alpha5beta1 complex and deposited its ligand fibronectin into the extracellular matrix. Function-blocking alpha5 antibodies attenuated migration, and caused massive apoptosis in EpRas cells undergoing TGFbeta1-induced EMT in collagen gels, but failed to affect EpRas- or FibRas-derived structures. We conclude that functional alpha5beta1 integrin is centrally implicated in EMT induction. Importantly, FibRas cells also failed to deposit the alpha6beta4 ligand laminin 5, suggesting that alpha6beta4 is no longer functional after EMT and replaced by mesenchymal integrins such as alpha5beta1.