Differential expression assay of chromosome arm 8p genes identifies Frizzled-related (FRP1/FRZB) and Fibroblast Growth Factor Receptor 1 (FGFR1) as candidate breast cancer genes

Abstract

Deletions and ampli®cations are frequent alterations of the short arm of chromosome 8 associated with various types of cancers, including breast cancers. This indicates the likely presence of tumor suppressor genes and oncogenes. In the present study, we have used the expressed sequence tag (EST) map of 8p11-21 to assemble a set of available cDNAs representing genes from this region. DNA arrays were prepared for expression analysis and search for genes potentially involved in breast cancer. Underexpresion in tumoral breast cells (versus normal breast) was observed for 15 transcripts. Among these, the Frizzled-related gene FRP1/FRZB, was turned o in 78% of breast carcinomas, suggesting that the lack of its product may be associated with malignant transformation. Overexpression in tumoral breast cells was observed for 13 genes. The FGFR1 gene, that encodes a tyrosine kinase receptor for members of the ®broblast growth factor family, was identi®ed as a good candidate for one ampli®cation unit. Taken together, our results demonstrate that such a strategy can rapidly identify genes with an altered pattern of expression and provide candidate genes for malignancies.

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

“…On the basis of their expression array analysis of chromosome 8p11-21 genes, Ugolini et al (1999) reported that expression of SFRP1 mRNA is frequently diminished or lost in breast carcinomas, and they also found that loss of SFRP1 occurs in more than 80% of invasive breast carcinomas, although not in the medullary type (Ugolini et al, 2001). Using immunohistochemical analysis, Klopocki et al (2004) found that expression of SFRP1 protein was absent in 46% of invasive breast tumours and in 43% of carcinoma in situ.…”

“…Lin et al (2000) also showed that nuclear and/or cytoplasmic staining of b-catenin correlated with elevated cyclin D1, which is one of the known targets of b-catenin/TCF transcription. However, mutation of APC, CTNNB1 or AXIN is rare in breast cancer, and thus the mechanism of Wnt signal activation in this disease is not fully understood.On the basis of their expression array analysis of chromosome 8p11-21 genes, Ugolini et al (1999) reported that expression of SFRP1 mRNA is frequently diminished or lost in breast carcinomas, and they also found that loss of SFRP1 occurs in more than 80% of invasive breast carcinomas, although not in the medullary type (Ugolini et al, 2001). Using immunohistochemical analysis, Klopocki et al (2004) found that expression of SFRP1 protein was absent in 46% of invasive breast tumours and in 43% of carcinoma in situ.…”

High-resolution analysis of chromosome rearrangements on 8p in breast, colon and pancreatic cancer reveals a complex pattern of loss, gain and translocation

“…The array CGH also suggests the region proximal to this deletion and before the centromere may also be amplified, but this was not investigated further. This region may include the ANK1 and PLAT genes which can be amplified separately (Ugolini et al, 1999).…”

“…This amplicon was present in 24% of primary breast tumours and found to correlate with poor survival (Garcia et al, 2005;Prentice et al, 2005). The long-suspected amplification target, FGFR1, was excluded from the current consensus amplicon and detected as amplified in fewer, 10-15%, of cases (Theillet et al, 1993;Ugolini et al, 1999;Prentice et al, 2005). Amplification of proximal 8p is also seen in other carcinomas (Veltman et al, 2003;Nakao et al, 2004).…”

“…In breast, for example, classical cytogenetic banding shows hsrs (homogeneously staining regions, i.e. large-scale amplifications) attached to 8p12 (Bernardino et al, 1998) and fluorescence in situ hybridization (FISH), CGH and Southern blotting show amplification generally in the region of 8p12 (Dib et al, 1995;Bautista and Theillet, 1998;Davidson et al, 2000), which often, but not invariably, includes FGFR1, and may occasionally extend as far distally as NRG1 (Ugolini et al, 1999). Recent array CGH studies that examine the 8p12 region in breast cancer have concentrated on the definition of the 8p12 amplicon (Ray et al, 2004;Garcia et al, 2005;Prentice et al, 2005).…”