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Background  Increased transcription of oncogenes like the epidermal growth factor receptor (EGFR) is frequently caused by amplification of the whole gene or at least of regulatory sequences. Aim of this study was to pinpoint mechanistic parameters occurring during  egfr  copy number gains leading to a stable EGFR overexpression and high sensitivity to extracellular signalling. A deeper understanding of those marker events might improve early diagnosis of cancer in suspect lesions, early detection of cancer progression and the prediction of  egfr  targeted therapies.    Methods  The basal-like/stemness type breast cancer cell line subpopulation MDA-MB-468 CD44 high /CD24 -/low , carrying high  egfr  amplifications, was chosen as a model system in this study. Subclones of the heterogeneous cell line expressing low and high EGF receptor densities were isolated by cell sorting. Genomic profiling was carried out for these by means of SNP array profiling, qPCR and FISH. Cell cycle analysis was performed using the BrdU quenching technique.    Results  Low and high EGFR expressing MDA-MB-468 CD44 + /CD24 -/low  subpopulations separated by cell sorting showed intermediate and high copy numbers of  egfr , respectively. However, during cell culture an increase solely for  egfr  gene copy numbers in the intermediate subpopulation occurred. This shift was based on the formation of new cells which regained  egfr  gene copies. By two parametric cell cycle analysis clonal effects mediated through growth advantage of cells bearing higher  egfr  gene copy numbers could most likely be excluded for being the driving force. Subsequently, the detection of a fragile site distal to the  egfr  gene, sustaining uncapped telomere-less chromosomal ends, the ladder-like structure of the intrachromosomal  egfr  amplification and a broader range of  egfr  copy numbers support the assumption that dynamic chromosomal rearrangements, like breakage-fusion-bridge-cycles other than proliferation drive the gain of  egfr  copies.    Conclusion  Progressive genome modulation in the CD44 + /CD24 -/low  subpopulation of the breast cancer cell line MDA-MB-468 leads to different coexisting subclones. In isolated low-copy cells asymmetric chromosomal segregation leads to new cells with regained solely  egfr  gene copies. Furthermore,  egfr  regain resulted in enhanced signal transduction of the MAP-kinase and PI3-kinase pathway. We show here for the first time a dynamic copy number regain in basal-like/stemness cell type breast cancer subpopulations which might explain genetic heterogeneity. Moreover, this process might also be involved in adaptive growth factor receptor intracellular signaling which support survival and migration during cancer development and progression.

Selective regain of egfr gene copies in CD44+/CD24-/lowbreast cancer cellular model MDA-MB-468