解放軍軍事醫(yī)學(xué)科學(xué)院與解放軍總醫(yī)院在乳腺癌內(nèi)分泌治療的耐藥機(jī)制研究中取得重大成果,，發(fā)現(xiàn)炎癥調(diào)控分子CUEDC2在乳腺癌細(xì)胞中過(guò)量表達(dá)導(dǎo)致了乳腺癌患者對(duì)內(nèi)分泌治療產(chǎn)生耐藥，并深入揭示了CUEDC2誘發(fā)耐藥的全新分子機(jī)制,，對(duì)于指導(dǎo)臨床治療具有重要意義,。
周濤、潘欣和邰艷紅作為共同第一作者的研究論文16日在國(guó)際權(quán)威學(xué)術(shù)期刊《自然醫(yī)學(xué)》在線(xiàn)發(fā)表并將于近期正式刊出,。此項(xiàng)研究工作是在國(guó)家自然科學(xué)基金重大研究計(jì)劃和國(guó)家973等項(xiàng)目資助下完成的,，張學(xué)敏是課題負(fù)責(zé)人和首席科學(xué)家。
據(jù)了解,，乳腺癌作為女性發(fā)病率最高的惡性腫瘤之一。近10年來(lái),，中國(guó)主要城市乳腺癌發(fā)病率增加了37%,，全國(guó)則以3%至4%的水平呈逐年上升趨勢(shì)。此外,，中國(guó)乳腺癌高峰發(fā)病年齡集中在45～55歲,，比世界平均水平早10～15年左右。
由于多數(shù)乳腺癌是雌激素依賴(lài)的惡性腫瘤,，因此內(nèi)分泌治療成為乳腺癌患者得以長(zhǎng)期生存的重要手段之一,。其中，他莫西芬是目前應(yīng)用最廣泛的乳腺癌內(nèi)分泌治療藥物,，通過(guò)與體內(nèi)雌激素競(jìng)爭(zhēng)性結(jié)合雌激素受體而抑制腫瘤細(xì)胞的生長(zhǎng),。但是，乳腺癌治療中存在的耐藥問(wèn)題大大影響了他莫西芬的乳腺癌臨床療效,，是導(dǎo)致乳腺癌臨床治療失敗的主要原因之一,。因此闡明耐藥機(jī)制已成為乳腺癌治療的一個(gè)亟待解決的重要科學(xué)問(wèn)題。
針對(duì)這一世界性難題,，張學(xué)敏教授帶領(lǐng)的課題組和解放軍總醫(yī)院韋立新教授帶領(lǐng)的課題組通力合作,，充分利用中國(guó)豐富的臨床病例資源,，開(kāi)展轉(zhuǎn)化醫(yī)學(xué)研究，從多個(gè)層次研究導(dǎo)致乳腺癌對(duì)內(nèi)分泌治療產(chǎn)生耐藥的分子機(jī)制,，闡釋了相關(guān)的信號(hào)轉(zhuǎn)導(dǎo)及其調(diào)控過(guò)程,，發(fā)現(xiàn)了導(dǎo)致乳腺癌耐藥的新標(biāo)志物，為克服乳腺癌耐藥提供了原創(chuàng)性的藥物新靶點(diǎn)和治療新思路,。（生物谷Bioon.com）
生物谷推薦原文：
Nature Medicine DOI:10.1038/nm.2369
Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer
Xin Pan,1, 5 Tao Zhou,1, 5 Yan-Hong Tai,2, 3, 5 Chenguang Wang,4 Jie Zhao,1 Yuan Cao,3 Yuan Chen,1 Pei-Jing Zhang,1 Ming Yu,1 Cheng Zhen,1 Rui Mu,1 Zhao-Fang Bai,1 Hui-Yan Li,1 Ai-Ling Li,1 Bing Liang,1 Zhao Jian,1 Wei-Na Zhang,1 Jiang-Hong Man,1 Yan-Fei Gao,1 Wei-Li Gong1 & Xue-Min Zhang1
Endocrine resistance is a major obstacle to hormonal therapy for breast cancers. Although reduced expression of estrogen receptor-α (ER-α) is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. Here we report that CUE domain–containing protein-2 (CUEDC2), a ubiquitin-binding motif–containing protein, is a key factor in endocrine resistance in breast cancer. We show that CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway. Through the study of specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between CUEDC2 and ER-α protein expression. Notably, subjects with tumors that highly expressed CUEDC2 had poor responsiveness to tamoxifen treatment and high potential for relapse. We further show that ectopic CUEDC2 expression impaired the responsiveness of breast cancer cells to tamoxifen. Therefore, our findings suggest that CUEDC2 is a crucial determinant of resistance to endocrine therapies in breast cancer.
