Down-Regulated Expression of Cytokeratin 18 Promotes Progression of Human Breast Cancer

Woelfle, Ute; Sauter, Guido; Santjer, Sonja; Brakenhoff, Ruud H.; Pantel, Klaus

doi:10.1158/1078-0432.ccr-03-0114

Cited by 126 publications

(118 citation statements)

References 32 publications

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“…Further support for the putative role of our RAMBAs as differentiating agents came from the findings that VN/14-1 caused a dose-dependent up-modulation (from four-to six-fold) of ER-a protein, another differentiation marker. The ability of these RAMBAs to induce differentiation in breast cancer cells may be of significance in light of recent findings which suggest that downregulated expressions of CK 18 (Korsching et al, 2002;Woelfle et al, 2004;Schaller and Buhler, 2005) and/or E-cadherin/ ER-a (Nass et al, 2000;Kowalsski et al, 2003) promote progression of human breast cancer. It should be noted that differentiated tumour cells exhibit low proliferative and metastatic potential.…”

Section: Discussionmentioning

confidence: 97%

“…The effects of these agents on the expression levels of markers associated with differentiation (CK 8/18 and ER-a) were investigated following established procedures (Jing et al, 1996;Korsching et al, 2002;Kim and Freeman, 2003;Woelfle et al, 2004). Breast cancer cells were treated with the indicated concentrations of ATRA or RAMBAs (VN/14-1, VN/50-1, VN/66-1 and VN/69-1) for 6 days or 4HPR for 4 days with renewal of media and compounds on day 3.…”

Section: Effects Of Rambas On Mcf-7 T-47d and Mda-mb-231 Cell Growthmentioning

confidence: 99%

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Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

et al. 2007

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Antitumour effects of retinoids are attributed to their influence on cell proliferation, differentiation, apoptosis and angiogenesis. In our effort to develop useful agents for breast cancer therapy, we evaluated the effects of four representative retinoic acid metabolism blocking agents (RAMBAs, VN/14-1, VN/50-1, VN/66-1 and VN/69-1) on growth inhibition of oestrogen receptor positive (ER þ ve, MCF-7 and T-47D) and oestrogen receptor negative (ER Àve, MDA-MB-231) human breast cancer cells. Additionally, we investigated the biological effects/molecular mechanism(s) underlying their growth inhibitory properties as well as their antitumour efficacies against MCF-7 and MCF-7Ca tumour xenografts in nude mice. We also assessed the effect of combining VN/14-1 and all-trans-retinoic acid (ATRA) on MCF-7 tumuor xenografts. The ER þ ve cell lines were more sensitive (IC 50 values between 3.0 and 609 nM) to the RAMBAs than the ER Àve MDA-MB-231 cell line (IC 50 ¼ 5.6 -24.0 mM). Retinoic acid metabolism blocking agents induced cell differentiation as determined by increased expression of cytokeratin 8/18 and oestrogen receptor-a (ER-a). Similar to ATRA, they also induced apoptosis via activation of caspase 9. Cell cycle analysis indicated that RAMBAs arrested cells in the G1 and G2/M phases and caused significant downregulation (480%) of cyclin D1 protein. In vivo, the growth of MCF-7 mammary tumours was dose-dependently and significantly inhibited (92.6%, Po0.0005) by VN/14-1. The combination of VN/14-1 and ATRA also inhibited MCF-7 breast tumour growth in vivo (up to 120%) as compared with single agents (Po0.025). VN/14-1 was also very effective in preventing the formation of MCF-7Ca tumours and it significantly inhibited the growth of established MCF-7Ca tumours, being as effective as the clinically used aromatase inhibitors, anastrozole and letrozole. Decrease in cyclin D1 and upregulation of cytokeratins, Bad and Bax with VN/14-1 may be responsible for the efficacy of this compound in inhibiting breast cancer cell growth in vitro and in vivo. Our results suggest that our RAMBAs, especially VN/14-1 may be useful novel therapy for breast cancer.

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Section: Discussionmentioning

confidence: 97%

Section: Effects Of Rambas On Mcf-7 T-47d and Mda-mb-231 Cell Growthmentioning

confidence: 99%

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

et al. 2007

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“…Dysregulation of keratin expression has long been recognized as a feature of epithelial tumor progression (25). For example, in breast epithelia, K8 and K18 are expressed in the differentiated compartment and are down-regulated in a high percentage of breast carcinomas, a feature that correlates with a worse prognosis (13,26,27). Similarly, micrometastatic cell lines derived from the bone marrow of breast cancer patients showed loss of cytokeratin expression with concomitant up-regulation of vimentin (28).…”

Section: Discussionmentioning

confidence: 99%

Keratin down-regulation in vimentin-positive cancer cells is reversible by vimentin RNA interference, which inhibits growth and motility

Paccione

Miyazaki

Patel

et al. 2008

Molecular Cancer Therapeutics

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At later stages of tumor progression, epithelial carcinogenesis is associated with transition to a mesenchymal phenotype, which may contribute to the more aggressive properties of cancer cells and may be stimulated by growth factors such as epidermal growth factor and transforming growth factor-B. Previously, we found that cells derived from a nodal metastatic squamous cell carcinoma are highly proliferative and motile in vitro and tumorigenic in vivo. In the current study, we have investigated the role of vimentin in proliferation and motility. Cells derived from nodal metastasis express high levels of vimentin, which is undetectable in tumor cells derived from a synchronous primary lesion of tongue. Vimentin expression was enhanced by epidermal growth factor and transforming growth factor-B both independently and in combination. Use of RNA interference resulted in the generation of stable cell lines that express constitutively low levels of vimentin. RNA interference-mediated vimentin knockdown reduced cellular proliferation, migration, and invasion through a basement membrane substitute by 3-fold compared with nontargeting controls. In addition, cells with reduced vimentin reexpressed differentiation-specific keratins K13, K14, and K15 as a result of increased gene transcription as judged by quantitative PCR and promoterreporter assays. Furthermore, cells in which vimentin expression was reduced showed a greatly decreased tumorigenic potential, as tumors developing from these cells were 70% smaller than those from control cells. The data suggest that reversal of the mesenchymal phenotype by inhibiting vimentin expression results in reexpression of epithelial characteristics and reduced tumor aggressiveness. [Mol Cancer Ther 2008;7(9):2894 -903]

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“…On the other hand, both of these cytokeratins are of the luminal type and their expressions in the breast luminal duct may determine the grade and invasiveness of the cancer [26]. Indeed, down-regulation of a luminal cytokeratin, CK18, has recently been shown to be associated with the progression of human breast cancer [27]. Up-regulation of the luminal cytokeratins in a non-invasive breast cancer cell is thus very interesting.…”

mentioning

confidence: 99%

Negative regulation of the expressions of cytokeratins 8 and 19 by SLUG repressor protein in human breast cells

Tripathi

Misra

Chaudhuri

2005

Biochemical and Biophysical Research Communications

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Invasiveness of tumor cells is often determined by the profile of their expressed genes. To determine the gene expression differences between an invasive and a non-invasive human breast tumor cells, we selected BT-549 (invasive) and MDA-MB-468 (non-invasive) cells, and compared their transcriptomes by cDNA microarray analysis. Among the significant differences in gene expressions, notable are the up-regulation of cytokeratins 8 and 19, and down-regulation of metallothioneins 1G and IL in MDA-MB-468 cells. Since MDA-MB-468 cells do not express SLUG, a member of a small family of E2-box-binding zinc finger silencer proteins, we studied whether the cytokeratin gene overexpressions in these cells are due to the absence of SLUG. Inducible expression of SLUG in MDA-MB-468 cells inhibited the expressions of the cytokeratin 8 and 19 but not others as was revealed by microarray analysis. Similarly, siRNA knock down of SLUG in BT-549 cells increased the expressions of those cytokeratin mRNAs. SLUG levels in the cell regulated the function of cytokeratins 8 and 19 gene promoters. We conclude that the expressions of cytokeratins and metallothioneins may be associated with the differential invasive behaviors of these breast tumor cells and SLUG may have regulatory roles in this process. KeywordsInvasiveness; Breast tumor; SLUG; Cytokeratin 8; Cytokeratin 19; Metallothionein 1G; Metallothionein 1L; siRNA; Microarray A serious gap in our understanding of cancer concerns malignancy and metastasis. We have yet to clearly identify gene defects that specifically permit cells to invade surrounding tissues, spread through the body, and form metastases. Local invasiveness requires a break down of the mechanisms that normally hold epithelial cells together. To determine the gene expression differences between an invasive and a non-invasive human breast tumor cells, we selected BT-549 (invasive) and MDA-MB-468 (non-invasive) cells, and compared their transcriptomes by cDNA microarray analysis. One of the known genotypic differences between these two cells is that BT-549 expresses the zinc finger repressor protein SLUG but the MDA-MB-468 cells do not [1]. Hence, we tested whether any gene overexpressed in the MDA-MB-468 cells is regulated by SLUG.We paid particular attention to SLUG because it is implicated as one of the determinants of tumor cell invasiveness [2][3][4][5][6]. This protein is a member of a superfamily of transcriptional regulators that are implicated in the formation of mesoderm and neural crest, as well as in We then overexpressed SLUG in MDA-MB-468 cells from a doxycycline-inducible promoter and compared the gene expression profile in the presence or absence of the inducer. We identified that cytokeratins 8 and 19 genes are repressed when SLUG expression is induced. We have verified the role of SLUG in regulating these cytokeratins by siRNA-mediated knock down of SLUG in BT-549 cells. We also report here our preliminary characterization of the promoters of these cytokeratin genes as it is regulated by SLUG exp...

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Down-Regulated Expression of Cytokeratin 18 Promotes Progression of Human Breast Cancer

Cited by 126 publications

References 32 publications

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

Keratin down-regulation in vimentin-positive cancer cells is reversible by vimentin RNA interference, which inhibits growth and motility

Negative regulation of the expressions of cytokeratins 8 and 19 by SLUG repressor protein in human breast cells

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