engleski

Cyclin D1 and nuclear EGFR in invasive ductal breast carcinoma

AIM: Advances in molecular medicine have facilitated identification of tumor markers that not only predict prognosis and therapeutic response but are a target of novel anticancer drugs. EGFR family receptors and cyclin D1 have been extensively studied in breast cancer, however systematic studies that examine protein expression and gene status all of these entities at same cohort of patients are lacking. Also emerging evidences suggest existence of direct EGFR signalling pathway which involves cellular transport of EGFR from cell membrane to the nucleus and transcriptional regulation of the target genes. Thus we examined protein expression and gene status of membrane EGFR (mEGFR), nuclear EGFR (nEGFR) and cyclin D1 using immunohistochemistry and fluorescent in situ hybridization (FISH) on tissue microarrays (TMA). MATERIAL AND METHODS: TMA were built from the cohort of 113 archival formalin fixed paraffin embedded invasive ductal carcinoma. Immunohistochemistry was performed for mEGFR, nEGFR and cyclin D1 with subsequent FISH analysis of EGFR and cyclin D1 gene status. RESULTS: In total 113 tumor samples were analyzed for nEGFR and we detected in 13 (11.5%) cases high (+++) percentage of tumor cells to be positive for nEGFR. Seven cases (6.2%) had moderate (++) percentage of tumor cells positive for nEGFR while 26 (23.0%) had low (+) percentage of tumor cells positive for nEGFR. On the other hand mEGFR overexpression was detected in only 2 (1.8%) cases. Cyclin D1 expression in examined group of tumors was as follows: 6 tumors (5.3%) were negative, 4 (3.5%) had low cyclin D1 expression, 31 (27.4%) moderate and 72 (63.7%) strong expression of cyclin D1 according to the Allred scoring method. EGFR gene amplification was found in 2 cases and CCND1 amplification in 15 cases. nEGFR correlated with tumor size (p= 0.0005), lymph node metastasis (p=0.0288), NPI (p=0.0011) and ER expression (p=0.0258) but the letter correlation was observed only in pre-menopausal group of patients. Cyclin D1 expression showed positive correlation with ER (p=0.0113) and inverse correlation with NPI (p=0.0309) and mEGFR (p=0.0201). CCND1 amplification also showed inverse correlation with mEGFR (p=0.0420). A strong correlation between mEGFR expression and gene amplification (p=0.0035), as well as cyclin D1 overexpression and gene amplification (p=0.0362) was demonstrated. On univariate analysis cyclin D1 expression showed a correlation with longer overall survival (OS) in pre-menopausal group and nEGFR correlated with shorter OS in whole cohort as well in pre-menopausal group of patients. Multivariate analysis revealed nEGFR to be independent prognostic factor and showed 3.4 times greater mortality risk for nEGFR+++ patients comparing to nEGFR negative patients (hazard ration = 3.402 ; p=0.0026). CONCLUSION: Our study confirms that strong cyclin D1 expression represents a good prognostic marker however high nEGFR staining showed worse OS in breast cancer patients.

ductal breast carcinoma; cyclin D1; EGFR; nuclear EGFR

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