JBC:研究者发现罕见乳腺癌耐药机制

　　

    生物通报道  近期伊利诺州立大学芝加哥医学院的研究人员揭示了罕见乳腺癌产生药物耐受的机制，他们的发现为药物耐受性乳腺癌的治疗提供了新的靶点。研究论文发表在《生物化学杂志》（JBC）上。

    大约有70%的乳腺癌表达雌激素受体(ER)。这些“ER阳性”肿瘤通常会对激素相关的治疗产生反应，例如他莫昔芬（tamoxifen）或芳香酶抑制剂。

    “我们感兴趣的是ER阳性肿瘤通常表现出显著的侵袭性和耐药性，”该研究的负责人、伊利诺州立大学芝加哥医学院生理学和生物物理学助理教授Jonna Frasor说。

    Frasor和她的同事们对ER阳性肿瘤中雌激素及炎症因子（又称细胞因子）反应基因进行了筛查，最终她们将研究焦点集中在药物转运蛋白基因上。药物转运蛋白通常可将化疗药物泵出肿瘤细胞，从而使肿瘤产生耐药性。

    Frasor 实验室的学生、论文的第一作者Madhumita Pradhan称他们意外地发现雌激素和炎性蛋白共同作用促进了肿瘤细胞的侵袭。而在大多数情况下雌激素通常都是起对抗炎症的作用。研究人员证实在乳腺癌细胞中一种炎性蛋白NFĸB和雌激素受体共同作用促进了转运蛋白基因的表达。

    启动子是基因的一个重要组成部分，控制着基因表达（转录）的起始时间和表达的程度。启动子就像“开关”，决定着基因的活动。启动子通常含有一些重要的序列称为顺式作用元件，当转录因子识别并结合这些顺式作用元件时，就可启动或调控基因的表达。

    “我们发现雌激素受体被招募到转运蛋白基因的启动子区域。一旦雌激素受体与转运蛋白基因启动子结合，它就将NFĸB招募到它自己的顺式反应元件上。NFĸB与雌激素受体启动子结合可使雌激素受体更加稳定，从而大大提高了转运蛋白基因的表达，”Frasor说。

    “我们证实炎症和雌激素可以促进乳腺癌的进展，这对于乳腺癌的治疗具有重要的意义，”Frasor说。

（生物通：何嫱）

原文摘要：
Proinflammatory Cytokines Enhance Estrogen-dependent Expression of the Multidrug Transporter Gene ABCG2 through Estrogen Receptor and NFκB Cooperativity at Adjacent Response Elements

Madhumita Pradhan, Leslie A. Bembinster, Sarah C. Baumgarten and Jonna Frasor

Constitutive activation of NFκB in estrogen receptor (ER)-positive breast cancer is associated with tumor recurrence and development of anti-estrogen resistance. Furthermore, a gene expression signature containing common targets for ER and NFκB has been identified and found to be associated with the more aggressive luminal B intrinsic subtype of ER-positive breast tumors. Here, we describe a novel mechanism by which ER and NFκB cooperate to up-regulate expression of one important gene from this signature, ABCG2, which encodes a transporter protein associated with the development of drug-resistant breast cancer. We and others have confirmed that this gene is regulated primarily by estrogen in an ER- and estrogen response element (ERE)-dependent manner. We found that whereas proinflammatory cytokines have little effect on this gene in the absence of 17β-estradiol, they can potentiate ER activity in an NFκB-dependent manner. ER allows the NFκB family member p65 to access a latent NFκB response element located near the ERE in the gene promoter. NFκB recruitment to the gene is, in turn, required to stabilize ER occupancy at the functional ERE. The result of this cooperative binding of ER and p65 at adjacent response elements leads to a major increase in both ABCG2 mRNA and protein expression. These findings indicate that estrogen and inflammatory factors can modify each other's activity through modulation of transcription factor accessibility and/or occupancy at adjacent response elements. This novel transcriptional mechanism could have important implications in breast cancer, where both inflammation and estrogen can promote cancer progression.

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