Abstract
BackgroundBoth phenotypic and cytogenetic variability have been reported for clones of breast carcinoma cell lines but have not been comprehensively studied. Despite this, cell lines such as MCF-7 cells are extensively used as model systems.MethodsIn this work we documented, using CGH and RNA expression profiles, the genetic variability at the genomic and RNA expression levels of MCF-7 cells of different origins. Eight MCF-7 sublines collected from different sources were studied as well as 3 subclones isolated from one of the sublines by limit dilution.ResultsMCF-7 sublines showed important differences in copy number alteration (CNA) profiles. Overall numbers of events ranged from 28 to 41. Involved chromosomal regions varied greatly from a subline to another. A total of 62 chromosomal regions were affected by either gains or losses in the 11 sublines studied. We performed a phylogenetic analysis of CGH profiles using maximum parsimony in order to reconstruct the putative filiation of the 11 MCF-7 sublines. The phylogenetic tree obtained showed that the MCF-7 clade was characterized by a restricted set of 8 CNAs and that the most divergent subline occupied the position closest to the common ancestor. Expression profiles of 8 MCF-7 sublines were analyzed along with those of 19 unrelated breast cancer cell lines using home made cDNA arrays comprising 720 genes. Hierarchical clustering analysis of the expression data showed that 7/8 MCF-7 sublines were grouped forming a cluster while the remaining subline clustered with unrelated breast cancer cell lines. These data thus showed that MCF-7 sublines differed at both the genomic and phenotypic levels.ConclusionsThe analysis of CGH profiles of the parent subline and its three subclones supported the heteroclonal nature of MCF-7 cells. This strongly suggested that the genetic plasticity of MCF-7 cells was related to their intrinsic capacity to generate clonal heterogeneity. We propose that MCF-7, and possibly the breast tumor it was derived from, evolved in a node like pattern, rather than according to a linear progression model. Due to their capacity to undergo rapid genetic changes MCF-7 cells could represent an interesting model for genetic evolution of breast tumors.
Highlights
Both phenotypic and cytogenetic variability have been reported for clones of breast carcinoma cell lines but have not been comprehensively studied
MCF-7-MVLN were transfected with an estrogen responsive element (ERE)-Luciferase construct [24] and selected for Gentamycin resistance, while both MCF7-MVLN-6ms7 and MCF-7-MVLN-6ms8 have been produced by a long term exposure of MCF-7-MVLN cells to 200 nM OH-TAM
We propose that MCF-7 cells contain an undetermined number of coexisting clones, out of which one possess stem clone potential and are responsible for the genetic oligoclonality
Summary
Both phenotypic and cytogenetic variability have been reported for clones of breast carcinoma cell lines but have not been comprehensively studied. Primary breast tumors are known for their elevated level of inter-tumor heterogeneity, an important body of data has brought evidence of intra-tumoral heterogeneity as well Such evidence stems from cytogenetic studies which have shown that cytogenetically unrelated clones can be found in breast tumors [1]. Flow cytometry has been another way to address the question of intratumoral heterogeneity, showing that breast tumors correspond to intricate admixture of tumor cells with different DNA contents (i.e. different ploidies) [4] These findings were extended by Bonsing and coworkers [5], who showed that diploid and aneuploid cells, concurently present in breast tumors, had a number of genetic anomalies in common. Heterogeneity is a major problem in mammary carcinogenesis and has important clinical implications in terms of prognosis and therapy
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