Expression of the HER family mRNA in breast cancer tissue and association with cell cycle inhibitors p21waf1 and p27kip1

Background: The HER family of the receptor tyrosine kinases epidermal growth factor receptor (EGFR), HER2, HER3 and HER4 are involved in the pathogenesis of many human malignancies. Although there is extensive literature on the expression of single HER-2 and EGFR receptors in breast cancer, little is known concerning the simultaneous expression at the mRNA level of these four receptors in human breast tissue and their influence in downstream signaling pathways that control cell cycle and proliferation. Materials and Methods: The mRNA expression pattern of the four HER-receptors has been investigated and correlated with the expression of the cyclin-dependent kinase (CDK) inhibitors p21(Waf1) and p27(Kip1) in 67 breast cancer specimens. Results: A positive correlation between HER-3 and HER-4 mRNA levels and a negative correlation between HER2 and HER-3 was found. Compared to normal breast tissue, all four receptors were overexpressed in breast tumors and the strongest overexpression was found for HER-3 (p=0.001). HER-4 expression was inversely related to histopathological grading (HPG), suggesting that elevated HER-4 mRNA expressions could be a biological marker of a more differentiated phenotype. The expression of p21(Waf1) protein was higher in HER-2-negative tumors, compared to HER-2-positive breast carcinomas. Compared to normal breast tissue, p21 Delta, the 19 kDa degraded form of p21 protein, was markedly expressed in breast cancer (p < 0.001). Conversely, p27(Kip1) was positively associated with HER-2 receptor and inversely associated with HER-3. Conclusion: The HER family members are overexpressed in breast cancer. Complex patterns of HER family expression were observed and the effect on cell cycle regulation was dependent on that pattern.