Prospective Study of Eukaryotic Initiation Factor 4E Protein Elevation and Breast Cancer Outcome

Abstract

ObjectiveTo validate the authors' initial hypothesis-generating observation that eukaryotic initiation factor 4E (eIF4E) protein elevation predicts a higher cancer recurrence rate in patients with stage 1 to 3 breast cancer. Summary Background DataTumor size and nodal status continue to be the two most important independent prognostic markers in breast cancer, despite well-documented limitations. In a previous smaller retrospective study, eIF4E, important in the regulation of protein synthesis of mRNAs with long or complex 5' untranslated regions, appeared promising as an independent predictor of breast cancer recurrence. MethodsSpecimens and clinical data from 191 patients with stage 1 to 3 breast cancer were accrued prospectively. Data collected include stage of disease, tumor grade, age at diagnosis, and menopausal status. Endpoints measured were disease recurrence and cancer-related death. eIF4E protein level was quantified using Western blot analysis. Immunohistochemical staining was used to determine estrogen receptor, progesterone receptor, and HER-2/neu receptor status. Statistical analysis include Cox proportional hazards model, log-rank test, Kaplan-Meier survival curve, Fisher exact test, and t test. ResultsPatients were divided into three groups based on tertile distribution of eIF4E: low, defined as less than 7.5-fold elevation (n ϭ 64); intermediate, defined as 7.5-to 14-fold elevation (n ϭ 61); and high, defined as more than 14-fold elevation (n ϭ 66). The relative risk for cancer recurrence with intermediate elevation was 4.1 times that of patients with low elevation. For patients with high elevation, the relative risk for recurrence was higher, at 7.2 times that of the low group. The relative risk for cancer-related death for high elevation was 7.3 times that of patients with low eIF4E. Using multivariate analysis, high eIF4E remained an independent predictor of cancer recurrence after adjusting for tumor size, tumor grade, nodal disease, estrogen receptor status, progesterone receptor status, and menopausal status. ConclusionsHigh eIF4E is an independent predictor of cancer recurrence in patients with stage 1 to 3 breast cancer. The relative risk for cancer recurrence increases with eIF4E protein elevation. High eIF4E elevation is also associated with an increased relative risk for cancer-related death.To date, the two most important independent prognostic markers in breast cancer continue to be tumor size and nodal status.1,2 However, systemic failure can and does occur in patients with small, node-negative tumors.3 Approximately two thirds of invasive breast carcinomas present without evidence of axillary lymph node involvement, but at least 25% of these carcinomas eventually recur.1,3 Conversely, more than 30% of node-positive breast carcinomas do not develop recurrent disease.1 These inherent deficiencies in the TNM staging system have necessitated the search for a prognostic marker in breast carcinoma, independent of tumor size and nodal status.Malignant transformation is a multistep proce...

The effect of p-4E-BP1 and p-eIF4E on cell proliferation in a breast cancer model

“…Tumorigenesis in transgenic eIF4E-expressing mice is markedly increased, leading to the development of lymphomas (30). This transforming activity of eIF4E has been associated with its phosphorylation (18,31) and with c-myc co-activation (30). In fact, eIF4E phosphorylation has been linked to suppression of apoptosis by an increase in the antiapoptotic protein MCL1 (18).…”

eIF4E – from translation to transformation

“…eIF4E is indeed overexpressed in many solid tumors and tumor cell lines. The list includes cancers of the colon, breast, bladder, lung, prostate, gastrointestinal tract, head and neck, Hodgkin's lymphomas and neuroblastomas (Kerekatte et al, 1995;Anthony et al, 1996;De Benedetti and Harris, 1999;Nathan et al, 1999;Rosenwald et al, 1999Rosenwald et al, , 2001Wang et al, 1999Wang et al, , 2001Li et al, 2002a). A role for eIF4E as a prognosis marker has also been suggested in certain cancers (reviewed in Thornton et al, 2003).…”

Controlling Gene Expression through RNA Regulons: The Role of the Eukaryotic Translation Initiation Factor eIF4E

“…20,[23][24][25][26] Increased levels of eIF4E are an indicator of poor prognosis in many of these including breast cancer. 27,28 eIF4E overexpression leads to oncogenic transformation of cell lines 29 and overexpression of eIF4E leads to increased tumour size and increased metastases in xenograft mouse models. 2 Transgenic mouse models of eIF4E overexpression show that these mice not only get cancer but also become chemo-resistant.…”