Proteins Associated With Poor Prognosis in Hormone Receptor-Positive Breast Cancer Identified

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Newswise — CHICAGO — Researchers have identified specific proteins involved in translation that when overexpressed or activated are associated with a poorer prognosis in hormone receptor-positive breast cancer, suggesting their role as prognostic markers and therapeutic targets, according to results presented at the AACR Annual Meeting 2012, held here March 31 - April 4.

“Overexpression or activation of some proteins involved in translation is associated with more aggressive node-positive breast cancers,” said Funda Meric-Bernstam, M.D., professor of surgical oncology at the University of Texas MD Anderson Cancer Center and medical director at the Institute of Personalized Cancer Therapy in Houston, Texas. “The results suggest that translational aberrations play an important role in cancer progression.”

Through analysis of tumors from 190 patients with stage 1 to stage 3 hormone receptor-positive breast cancer, the researchers found that increased phosphorylation of ribosomal protein S6 and translation initiation factor 4E-binding protein 1, increased expression of eukaryotic elongation factor 2 kinase and decreased expression of programmed cell death protein 4 were associated with poor prognosis in hormone receptor-positive breast cancer.

“Gene expression involves translation of messenger RNAs into protein. The rate of translation is under critical control at many levels; however, recently, several abnormalities in translation have been described in cancer,” said Meric-Bernstam. “We used a functional proteomics approach to quantify the expression and phosphorylation of several factors associated with translation. Several of these proteins have been suggested to play a role in tumor aggressiveness.”

The markers identified are regulated by the PI3K/mTOR signaling pathway, a key oncogenic pathway activated in breast cancer and other cancers, according to Meric-Bernstam. Novel inhibitors of the pathway are being investigated in clinical trials.

“There are recent phase III clinical trial data suggesting that inhibiting mTOR signaling with everolimus, an mTOR inhibitor, in addition to endocrine therapy with aromatase inhibitors improves progression-free survival in hormone receptor-positive breast cancer,” Meric-Bernstam said. “Activation of the pathway conferring poor prognosis provides rationale as to why pathway inhibitors improve outcome.”

The study was funded by an AACR–Stand Up To Cancer Dream Team Award, Susan G. Komen for the Cure, the Society of Surgical Oncology Clinical Investigator Award and the National Institutes of Health Cancer Center Grant.

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Presenter: Funda Meric-Bernstam, M.D.

Abstract Number: CT-03

Title: Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer.

Author Block: Funda Meric-Bernstam1, Huiqin Chen1, Argun Akcakanat1, Kim-Anh Do1, Ana Lluch2, Bryan Hennessy3, Gabriel Hortobagyi1, Gordon Mills1, Ana Gonzalez-Angulo1. 1UT M.D. Anderson Cancer Ctr., Houston, TX; 2Hospital Clinico Universitario de Valencia, Valencia, Spain; 3Beaumont Hospital, Dublin, Ireland.

Purpose: Translation initiation is activated in cancer through increase in eukaryotic initiation factor 4E (eIF4E), eIF4G, phosphorylated eIF4E-binding protein (p4E-BP1) and ribosomal protein S6 (pS6), and decreased programmed cell death protein 4 (pdcd4), a translational inhibitor. Further, translation elongation is deregulated though alterations in eukaryotic elongation factor 2 (eEF2) and eEF2 kinase (eEF2K). We sought to determine the association of these translational aberrations with clinical-pathologic factors and survival outcomes in hormone receptor-positive breast cancer.Methods: Primary tumors were collected from 190 patients with stage I-III hormone receptor-positive breast cancer. Expression of eIF4E, eIF4G, 4E-BP1, p4E-BP1 T37/46, p4E-BP1 S65, p4E-BP1 T70, S6, pS6 S235/236, pS6 S240/244, pdcd4, eEF2 and eEF2K was assessed by reverse phase protein arrays.: Univariable and multivariable analyses for recurrence-free survival (RFS) and overall survival (OS) were performed.Results: High eEF2, S6, pS6 S240/244, p4E-BP1 T70, and low pdcd4 were significantly associated with node-positivity. Median follow-up for alive patients was 96 months.High p4E-BP1 T36/47, p4E-BP1 S65, p4E-BP1 T70 and 4E-BP1 were associated with worse RFS. High p4E-BP1 T70 and pS6 S235/236, and low pdcd4, were associated with worse OS. In multivariable analysis, in addition to positive nodes, p4E-BP1 S65 remained a significant predictor of RFS (HR=1.62, 95%CI=1.13-2.31; P=0.008). In addition to age, pS6 S235/236 (HR=1.73, 95%CI=1.03-2.90, P=0.039), eEF2K (HR=2.19, 95%CI=1.35-3.56, P=0.002) and pdcd4 (HR=0.42, 95%CI=0.25-0.70, P=0.001) were associated with OS.Conclusions: Increased pS6, p4E-BP1, eEF2K and decreased pdcd4 are associated with poor prognosis in hormone receptor-positive breast cancer; suggesting their role as prognostic markers and therapeutic targets.