翻訳異常が、がんの進行に重要な役割を果たしている可能性がある

ホルモン受容体陽性乳がんの予後不良に関連した蛋白が発見された

Proteins associated with poor prognosis in hormone receptor-positive breast cancer identified

過剰発現したり活性化されたりするとホルモン受容体陽性乳がんの予後を不良とする、翻訳に関わる特異的な蛋白が発見されたとのスタディ結果が2012年AACR学会で発表された。筆者らは、翻訳に関わるいくつかの蛋白の過剰発現または活性化が進行の速いリンパ節転移陽性乳がんと関連することを強調している。ステージ1～3のホルモン受容体陽性乳がん患者190人の腫瘍解析を通して研究者らは、リボソーマル蛋白S6および翻訳開始因子4E結合蛋白1のリン酸化の増加、真核細胞伸長因子 2キナーゼ発現の増加およびプログラムされた細胞死蛋白4発現減少の全てがホルモン受容体陽性乳がんの予後不良に関連していることを発見した。この同定されたマーカーは、乳がんおよび他のがんで活性化されている重要な発がん性パスウェイであるPI3K/mTORパスウェイにより制御されていることを見出した。この結果は、翻訳異常ががん進行において重要な役割を果たしていることを示唆している。

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.

"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.