8q24 Copy number gains and expression of the c-myc mRNA stabilizing protein CRD-BP in primary breast carcinomas.

Abstract

The coding region determinant binding protein (CRD-BP) was isolated by virtue of its high affinity to the c-myc mRNA coding region stability determinant and shown to shield this message from nucleolytic attack, prolonging its half-life. CRD-BP is normally expressed during fetal life but is also activated de novo in tumors. Considering that aberrant CRD-BP expression may represent an additional mechanism interfering with c-myc regulation, we screened 118 primary breast carcinomas for CRD-BP expression, 60 of which had also been analyzed by comparative genomic hybridization (CGH). Copy number gains encompassing 8q24, the chromosome band that contains the c-myc locus, were detected in 48.3% (29/60) of tumors, whereas gains involving band 17q21, which contains the CRD-BP locus, were observed in 18.3% (11/60) of tumors. CRD-BP expression was detected in 58.5% (69/118) of tumors, implying mechanisms of activation alternative to gene amplification. Altogether, some 75% of the tumors had alterations pertaining to c-myc since they either harbored 8q24 gains and/or expressed CRD-BP. Significant associations were detected between CRD-BP expression and the absence of estrogen receptors (p = 0.005) and between the presence of 8q24 gains and an increased number of genomic changes as measured by CGH (p = 0.0017). Tumors were divided into 4 groups according to CRD-BP expression and 8q24 gains. The odds for tumors having both characteristics to be classified as poorly differentiated (grade III vs. grade I and II) were 19.6 times the corresponding odds for tumors neither expressing CRD-BP nor harboring 8q24 gains. For tumors either harboring 8q24 gains only or expressing CRD-BP alone, the corresponding odds were 6.4 and 3, respectively.