Nuclear EGFR in ductal invasive breast cancer: correlation with cyclin-D1 and prognosis

Abstract

The epidermal growth factor receptor (EGFR)-family and cyclin-D1 have been extensively studied in breast cancer; however systematic studies that examine protein expression and gene status in the same cohort of patients are lacking. Also emerging evidences suggest existence of a direct EGFR-signaling pathway, which involves cellular transport of EGFR from cell membrane to the nucleus, and transcriptional regulation of the target genes. Thus, we examined the protein expression of membrane EGFR, nuclear EGFR, cyclin-D1 and the corresponding gene status in 113 breast carcinomas by immunohistochemistry and fluorescence in situ hybridization using tissue microarrays. Membrane EGFR overexpression and EGFR gene amplification were detected in 2% cases, while nuclear EGFR was detected in 40% of cases, with 12% having high nuclear EGFR staining. Nuclear EGFR correlated with tumor size (P ¼ 0.0005), lymph node metastasis (P ¼ 0.0288), Nottingham prognostic index (P ¼ 0.0011) and estrogen receptor (ER) expression (P ¼ 0.0258) but the letter correlation was observed only in premenopausal group of patients. Strong cyclin-D1 expression and cyclin-D1 gene (CCND1) amplification were found in 64 and 13% of the cases, respectively. Cyclin-D1 expression showed positive correlation with ER (P ¼ 0.0113) and inverse correlation with Nottingham prognostic index (P ¼ 0.0309) and membrane EGFR (P ¼ 0.0201). CCND1 amplification also showed inverse correlation with membrane EGFR (P ¼ 0.0420). A strong correlation between membrane EGFR expression and gene amplification (P ¼ 0.0035), as well as cyclin-D1 overexpression and gene amplification (P ¼ 0.0362), was demonstrated. On univariate analysis cyclin-D1 expression showed a correlation with longer overall survival in the premenopausal group and nuclear EGFR correlated with shorter overall survival in whole cohort as well in the premenopausal group of patients. Multivariate analysis revealed nuclear EGFR to be an independent prognostic factor and showed 3.4 times greater mortality risk for nuclear EGFR þ þ þ patients as compared with nuclear EGFR negative patients (hazard ratio ¼ 3.402; P ¼ 0.0026).

CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response

“…After overnight hybridization at 37 1C, slides were washed and CCND1/Cyclin D1 in bladder cancer counterstained with DAPI II (125 ng/ml, Vysis) in an antifading solution. A minimum of 25 non-overlapping nuclei were evaluated on each spot, and the individual spot was considered normal or amplified according to the CCND1/CEP11 fluorescence ratios o2 or Z2 18 (Figures 1a and b).…”

“…[14][15][16] However, amplification does not necessarily leads to protein overexpression, suggesting complex expression mechanisms. [17][18][19] In bladder cancer, information on frequency of CCND1/CyclinD1 alterations and their clinical relevance are limited. The prognostic impact has primarily been evaluated in non-muscle invasive bladder cancer for CyclinD1 and with regard to recurrence-and progression-free survival.…”

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

“…21,24 Clinical studies have indicated that increased nEGFR expression is associated with poor prognosis. 25,26 The nuclear translocation of EGFR is initiated by ligandinduced endocytosis. 27 Endosome-associated EGFR is recognized by importin b in the cytoplasm and is then transported to the inner nuclear membrane (INM) via the INTERNET (integral trafficking from the ER to the nuclear envelope transport) mechanism.…”

Membrane-bound Trafficking Regulates Nuclear Transport of Integral Epidermal Growth Factor Receptor (EGFR) and ErbB-2

“…One gradually discovered example of MRIN RTKs, the nuclear EGF receptor (EGFR) family, is involved in multiple cellular functions, including transcriptional regulation, cell proliferation, DNA repair, and chemoand radio-resistance (2)(3)(4)(5)(6)(7)(8)(9)(10). Nuclear EGFR has also been shown to associate with poor prognosis in several cancer types, such as breast cancer, ovarian cancer, and oropharyngeal and esophageal squamous cell carcinomas (11)(12)(13)(14)(15)(16).…”