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Stromelysin-3 over-expression enhances tumourigenesis in MCF-7 and MDA-MB-231 breast cancer cell lines: involvement of the IGF-1 signalling pathway.

ABSTRACT: BACKGROUND: Stromelysin-3 (ST-3) is over-expressed in the majority of human carcinomas including breast carcinoma. Due to its known effect in promoting tumour formation, but its impeding effect on metastasis, a dual role of ST-3 in tumour progression, depending on the cellular grade of dedifferentiation, was hypothesized. METHODS: The present study was designed to investigate the influence of ST-3 in vivo and in vitro on the oestrogen-dependent, non-invasive MCF-7 breast carcinoma cell line as well as on the oestrogen-independent, invasive MDA-MB-231 breast carcinoma cell line. Therefore an orthotopic human xenograft tumour model in nude mice, as well as a 3D matrigel cell culture system, were employed. RESULTS: Using both in vitro and in vivo techniques, we have demonstrated that over-expression of ST-3 in MCF-7 and MDA-MB-231 cells leads to both increased cell numbers and tumour volumes. This observation was dependent upon the presence of growth factors. In particular, the enhanced proliferative capacity was in MCF-7/ST-3 completely and in MDA-MB-231/ST-3 cells partially dependent on the IGF-1 signalling pathway. Microarray analysis of ST-3 over-expressing cells revealed that in addition to cell proliferation, further biological processes seemed to be affected, such as cell motility and stress response. The MAPK-pathway as well as the Wnt and PI3-kinase pathways, appear to also play a potential role. Furthermore, we have demonstrated that breast cancer cell lines of different differentiation status, as well as the non-tumourigenic cell line MCF-10A, have a comparable capability to induce endogenous ST-3 expression in fibroblasts. CONCLUSION: These data reveal that ST-3 is capable of enhancing tumourigenesis in highly differentiated "early stage" breast cancer cell lines as well as in further progressed breast cancer cell lines that have already undergone epithelial-mesenchymal transition. We propose that ST-3 induction in tumour fibroblasts leads to the stimulation of the IGF-1R pathway in carcinoma cells, thus enhancing their proliferative capacity. In addition, further different cellular processes seem to be activated by ST-3, possibly accounting for the dual role of ST-3 in tumour progression and metastasis.

SUBMITTER: Kasper G

PROVIDER: S-EPMC1783860 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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Stromelysin-3 over-expression enhances tumourigenesis in MCF-7 and MDA-MB-231 breast cancer cell lines: involvement of the IGF-1 signalling pathway.

Kasper Grit G Reule Matthias M Tschirschmann Miriam M Dankert Niels N Stout-Weider Karen K Lauster Roland R Schrock Evelin E Mennerich Detlev D Duda Georg N GN Lehmann Kerstin E KE

BMC cancer 20070117

<h4>Background</h4>Stromelysin-3 (ST-3) is over-expressed in the majority of human carcinomas including breast carcinoma. Due to its known effect in promoting tumour formation, but its impeding effect on metastasis, a dual role of ST-3 in tumour progression, depending on the cellular grade of dedifferentiation, was hypothesized.<h4>Methods</h4>The present study was designed to investigate the influence of ST-3 in vivo and in vitro on the oestrogen-dependent, non-invasive MCF-7 breast carcinoma c ...[more]

PMID: 17233884

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Project description:Long non-coding RNAs (lncRNAs) are involved in a range of biological processes, such as cellular differentiation, migration, apoptosis, invasion, proliferation, and transcriptional regulation. The aberrant expression of lncRNAs plays a significant role in several cancer types. Aurora kinases are increasingly expressed in various malignancies; accordingly, the inhibition of these enzymes may represent a novel approach for the treatment of various cancers. CCT137690, an Aurora kinase inhibitor, displays an anti-proliferative activity in human cancer cell lines. The aim of the present study was to investigate the anti-proliferative and cytotoxic effects of CCT137690 on estrogen receptor (ER)-positive human breast cancer cell line (MCF-7) and ER-negative human breast cancer cell line (MDA-MB-231). In addition, this study was targeted toward determining the changes induced in lncRNA expression levels following the initiation of Aurora kinase inhibitor treatment. The cytotoxic effects of CCT137690 were determined by means of the xCELLigence system. Furthermore, the anti-proliferative role of CCT137690 in breast cancer was investigated by checking the changes in lncRNA expression profiles using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The half-maximal inhibitory concentrations (IC50) of CCT137690 were determined as 4.5 ?M (MCF-7) and 7.27 ?M (MDA-MB-231). Several oncogenic lncRNAs (e.g., PRINS, HOXA1AS, and NCRMS) were downregulated in both ER-negative and ER-positive cell lines. On the other hand, tumor suppressor lncRNAs (e.g., DGCR5 and IGF2AS) were upregulated in the ER-positive cell line. After CCT137690 treatment, HOXA11AS and PCAT-14 lncRNAs were downregulated in the ER-positive cell lines. In addition, MER11C, SCA8, BC200, HOTAIR, PCAT-1, UCA1, SOX2OT, and HULC lncRNAs were downregulated in the ER-negative cell lines. The results of the present study indicated that Aurora kinase inhibitor CCT137690 could be a potential anti-cancer agent for breast cancer treatment.

Project description:We used microarrays to detail the global programme of gene expression for MCF-7 and MDA-MB-231 and revealed the correlation between the methylation state of various genomic components and gene expression level. The expression analyses of the two breast cancer cell lines are a part of the whole study. The summary of our study is as follows: We establish a technique, called modified methylation-specific digital karyotyping (MMSDK) based on methylation-specific digital karyotyping (MSDK) with a novel sequencing approach. Briefly, after a tandem digestion of genomic DNA with a methylation-sensitive mapping enzyme and a fragmenting enzyme, short sequence tags are obtained. These tags are amplified, followed by direct, massively parallel sequencing (Solexa 1G Genome Analyzer). This method allows high-throughput and low-cost genome-wide DNA methylation mapping. We applied this method to investigate global DNA methylation profiles for widely used breast cancer cell lines, MCF-7 and MDA-MB-231, which are representatives for luminal-like and mesenchymal-like cancer types, respectively. By comparison, a highly similar overall DNA methylation pattern was revealed for the two cell lines. However a cohort of individual genomic loci with significantly different DNA methylation profile between two cell lines was identified. Furthermore, we revealed a genome-wide significant correlation between gene expression and the methylation status of gene promoters with CpG islands (CGIs) in the two cancer cell lines, and a correlation of gene expression and the methylation status of promoters without CGIs in MCF-7 cells. Experiment Overall Design: Breast cancer cell lines, MCF-7 and MDA-MB-231, were selected for the study of the impact of DNA methylation on gene expression regulation. Total RNA extraction was performed for both cell lines and hybridization was carried out using Affymetrix microarrays. We developed a modified methylation-specific digital karyotyping (MSDK) to obtain DNA methylation profiling genome wide. Then, we combined the analysis of DNA methylation data and gene expression data to reveal a correlation between epigenetic and transcriptional features genome wide.

Dataset Information

Stromelysin-3 over-expression enhances tumourigenesis in MCF-7 and MDA-MB-231 breast cancer cell lines: involvement of the IGF-1 signalling pathway.

Publications

Stromelysin-3 over-expression enhances tumourigenesis in MCF-7 and MDA-MB-231 breast cancer cell lines: involvement of the IGF-1 signalling pathway.

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