EGFR, HER-2/neu, Cyclin D1, p21 and p53 in Correlation to Cell Proliferation and Steroid Hormone Receptor Status in Ductal Carcinoma in situ of the Breast

Abstract

Abnormalities in G1/S transition in cell cultures have been attributed to alterations in ErbB (erythroblastic leukaemia viral [v-erb-b] oncogene homologue, avian) signalling, cyclin D1 overexpression or disturbance of the p21(WAF1) (p21)-mediated cell cycle arrest induced by p53. To investigate the significance of these mechanisms on an early stage of human breast tumour growth, we studied the expression of EGFR (ErbB1), HER-2/neu (ErbB2), cyclin D1, p21 and p53 as well as oestrogen (ER) and progesterone receptor (PgR) in paraffin sections of 45 ductal carcinoma in situ (DCIS) by immunohistochemistry. Cell proliferation was assessed by immunohistochemical quantification of Ki-67. Five cases with cyclin D1 overexpression were analysed by FISH for CCND1 amplification. Increased proliferative activity was observed in 46% of DCIS. It was correlated with the expression of EGFR and HER-2/neu (p < 0.05), but neither with cyclin D1 and p21 overexpression nor with p53 accumulation. ErbB positive status was associated with p21 overexpression (p < 0.05). In addition we found a correlation between the overexpression of p21 and cyclin D1 restricted to ErbB-positive cases (p = 0.013). ErbB-negative tumours with increased proliferative activity were ER and cyclin D1 positive. No CCND1 amplification was detected in the analysed cases. In conclusion, our data support that EGFR and HER-2/neu play an important role in cell cycle control in DCIS. p21 appears to be a potential mediator of ErbB signalling. We propose that cyclin D1 could be indirectly induced by ErbB signalling through p21. Besides, ER-mediated upregulation of cyclin D1 seems to be a possible mechanism of maintaining cell proliferation in DCIS in case of EGFR- and HER-2/neu-negativity.

The expression of FHIT, PCNA and EGFR in benign and malignant breast lesions

“…In contrast, overexpression of the mitogenic signalling mediator EGFR, indicative of abnormalities in the commitment of G1 to S phase in the cell cycle, was found in 30% of breast lesions, predominantly in invasive carcinoma (53%). Similar rates of EGFR overexpression have been reported previously in DCIS and invasive carcinoma (Knoop et al, 2001;Lebeau et al, 2003). The causes of EGFR overexpression are not well understood but aneusomy of chromosome 7 on which the EGFR gene is located does not relate directly to EGFR protein overexpression (Bhargava et al, 2005;Sauer et al, 2005).…”

Intraepithelial Neoplasia of Breast

“…p53 mutations/accumulation are present in a significant percentage of DCIS cases (Lebeau et al 2003;Poller et al 1993), especially in the comedo type (O'Malley et al 1994). However, the clinical significance of p53 accumulation remains still elusive; although it has been found to influence the proliferation rate (Rudas et al 1997), a recent study showed that it does not affect the proliferation rate of the DCIS lesion per se (Lebeau et al 2003).…”

“…However, the clinical significance of p53 accumulation remains still elusive; although it has been found to influence the proliferation rate (Rudas et al 1997), a recent study showed that it does not affect the proliferation rate of the DCIS lesion per se (Lebeau et al 2003). Is worth noting that the coexistence of DCIS with IDC is not associated with a different degree of p53 immunostaining (Myonlas et al 2005).…”

“…VEGF is a potent angiogenic growth factor, commonly involved in tumor-induced angiogenesis, with a putative therapeutic significance in the context of breast cancer (Lebeau et al 2003). Interestingly, VEGF gene polymorphisms have been associated with modified breast cancer risk in various populations (Jacobs et al 2006) Viacava et al (Viacava et al 2004) have thoroughly examined the angiogenesis in precursor and preinvasive lesions.…”

Role of the progesterone receptor (PR) in the regulation of inflammatory response pathways and aromatase in the breast

“…Breast tumors that are PR(-) have a much higher proliferation rate and are more likely to manifest increased expression of the tumorigenic prognostic indicators, HER-2/neu and EGFR, than PR(+) tumors [56][57][58][59]. PR exists as three major isoforms, PR-A (94 kDa), PR-B (114 kDa) [60] and PR-C (60 kDa) [61].…”