Purpose: Deregulation of key cellular pathways is fundamental for the survival and expansion of neoplastic cells. In cancer, regulation of gene transcription can be mediated in a variety of ways. The purpose of this study was to assess the impact of gene dosage on gene expression patterns, the effect of other mechanisms on transcriptional levels, and to associate these genomic changes to clinicopathological parameters. Experimental Design: We screened 97 invasive diploid breast tumors for DNA copy number alterations and changes in transcriptional levels using array comparative genomic hybridization and expression microarrays, respectively. Results: The integrative analysis identified an increase in the overall number of genetic alterations during tumor progression and fifteen specific genomic regions with aberrant DNA copy numbers in at least 25% of the patient population, i.e. 1q22, 1q22-q23.1, 1q25.3, 1q32.1, 1q32.1-q32.2, 8q21.2-q21.3, 8q22.3, 8q24.3, and 16p11.2 were recurrently gained, while 11q25, 16q21, 16q23.3, and 17p12 were frequently lost (P<0.01). An examination of the expression patterns of genes mapping within the detected genetic aberrations identified 47 unique genes and 1 Unigene cluster significantly correlated between the DNA and relative mRNA levels. In addition, more malignant tumors with normal gene dosage levels displayed a recurrent over-expression of UBE2C, S100A8 and CBX2, and down-regulation of LOC389033, STC2, DNALI1, SCUBE2, NME5, SUSD3, SERPINA11, AZGP1 and PIP. Conclusions: Taken together, our findings suggest that the dysregulated genes identified here are critical for breast cancer initiation and progression, which could be used as novel therapeutic targets for drug development to complement classical clinicopathological features.
- Received April 7, 2010.
- Revision received May 19, 2010.
- Accepted June 3, 2010.