Abstract
BackgroundStromelysin-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.MethodsThe 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.ResultsUsing 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.ConclusionThese 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.
Highlights
Stromelysin-3 (ST-3) is over-expressed in the majority of human carcinomas including breast carcinoma
ST-3 was discovered more than a decade ago and assigned to the family of matrix metalloprotease (MMP) due to sequence homologies, no extracellular matrix (ECM) component has yet been identified that is cleaved by full length human ST-3 [10]
Whether ST-3 expression in fibroblasts is induced by epithelial cells of different tumourigenic and invasive potential, the breast cancer cell lines MCF-7, MDA-MB-468 and MDA-MB-231 and the non-tumourigenic, immortalized cell line MCF-10A were co-cultured with primary breast tumour fibroblasts
Summary
Stromelysin-3 (ST-3) is over-expressed in the majority of human carcinomas including breast carcinoma. Other studies, performed in an ST-3 knock out mouse model and in human xenograft models of ST-3 over-expressing MCF-7 cells demonstrate that the activation of ST-3 leads to a lower percentage of apoptotic cells in the induced tumours [15,16]. According to these results, the generation of MMTV-ras transgenic mice in an ST-3 deficient genotype results in the development of less and smaller primary tumours [17]. It has been shown that during involution, ST-1 and ST-2 is up-regulated in matrilysin knock out mice, and that matrilysin and ST-2 expression is elevated in ST-1 deficient mice [19]
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