The growth response to androgen receptor signaling in ERα-negative human breast cells is dependent on p21 and mediated by MAPK activation.
The growth response to androgen receptor signaling in ERα-negative human breast cells is dependent on p21 and mediated by MAPK activation.
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DOI：
10.1186/bcr3112
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发表时间：
2012-02-09
期刊：
影响因子：
--
通讯作者：
Park BH
中科院分区：
文献类型：
--
作者：
Garay JP;Karakas B;Abukhdeir AM;Cosgrove DP;Gustin JP;Higgins MJ;Konishi H;Konishi Y;Lauring J;Mohseni M;Wang GM;Jelovac D;Weeraratna A;Sherman Baust CA;Morin PJ;Toubaji A;Meeker A;De Marzo AM;Lewis G;Subhawong A;Argani P;Park BH
尽管已经描述了人类乳腺癌中雄激素受体（AR）的高频率表达，但是利用这些知识进行治疗一直具有挑战性。这部分是因为雄激素可以抑制或刺激乳腺癌临床前模型中的细胞增殖。此外，许多乳腺癌共表达可影响AR信号传导的其他类固醇激素受体，进一步混淆雄激素对乳腺癌细胞的作用。为了在人类乳腺上皮细胞中创建更好定义的AR信号传导模型，我们采用雌激素受体（ER）-α阴性和孕酮受体（PR）阴性人类乳腺上皮细胞系，包括癌性和非癌性细胞，并将其改造为表达AR，从而允许明确研究AR信号传导。我们克隆了人AR的全长cDNA，并在MCF-10A非致瘤性人乳腺上皮细胞和MDA-MB-231人乳腺癌细胞中表达该转基因。我们使用各种测定表征了对AR配体结合的反应，并使用表达AR的同基因MCF-10A p21敲除细胞系来证明p21在介导人乳腺上皮细胞中对AR信号传导的增殖反应中的需要。我们发现，从AR和表皮生长因子受体（EGFR）信号的丝裂原活化蛋白激酶（MAPK）通路的超活化导致生长抑制反应，而从AR或EGFR激活MAPK信号导致细胞增殖。此外，p21基因敲除研究证实，MAPK途径的AR信号传导/激活依赖于p21。这些研究为分析缺乏ERα/PR表达的人乳腺上皮细胞中AR信号转导提供了一种新的模型，提供了一种没有ERα/PR串扰潜在混杂效应的实验系统。使用这个系统，我们提供了一个机制解释以前的观察归因于AR信号在人类乳腺癌细胞中的双重作用。由于之前的报告表明，大约40%的乳腺癌可能缺乏p21表达，我们的数据还确定了利用AR作为乳腺癌治疗靶点的潜在新警告。
Although a high frequency of androgen receptor (AR) expression in human breast cancers has been described, exploiting this knowledge for therapy has been challenging. This is in part because androgens can either inhibit or stimulate cell proliferation in pre-clinical models of breast cancer. In addition, many breast cancers co-express other steroid hormone receptors that can affect AR signaling, further obfuscating the effects of androgens on breast cancer cells. To create better-defined models of AR signaling in human breast epithelial cells, we took estrogen receptor (ER)-α-negative and progesterone receptor (PR)-negative human breast epithelial cell lines, both cancerous and non-cancerous, and engineered them to express AR, thus allowing the unambiguous study of AR signaling. We cloned a full-length cDNA of human AR, and expressed this transgene in MCF-10A non-tumorigenic human breast epithelial cells and MDA-MB-231 human breast-cancer cells. We characterized the responses to AR ligand binding using various assays, and used isogenic MCF-10A p21 knock-out cell lines expressing AR to demonstrate the requirement for p21 in mediating the proliferative responses to AR signaling in human breast epithelial cells. We found that hyperactivation of the mitogen-activated protein kinase (MAPK) pathway from both AR and epidermal growth factor receptor (EGFR) signaling resulted in a growth-inhibitory response, whereas MAPK signaling from either AR or EGFR activation resulted in cellular proliferation. Additionally, p21 gene knock-out studies confirmed that AR signaling/activation of the MAPK pathway is dependent on p21. These studies present a new model for the analysis of AR signaling in human breast epithelial cells lacking ERα/PR expression, providing an experimental system without the potential confounding effects of ERα/PR crosstalk. Using this system, we provide a mechanistic explanation for previous observations ascribing a dual role for AR signaling in human breast cancer cells. As previous reports have shown that approximately 40% of breast cancers can lack p21 expression, our data also identify potential new caveats for exploiting AR as a target for breast cancer therapy.
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绝经后妇女的雄激素受体表达和乳腺癌存活。
DOI：
10.1158/1078-0432.ccr-10-2021
发表时间：
2011-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hu R;Dawood S;Holmes MD;Collins LC;Schnitt SJ;Cole K;Marotti JD;Hankinson SE;Colditz GA;Tamimi RM
通讯作者：
Tamimi RM
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
3.8
作者：
Castellano, Isabella;Allia, Elena;Sapino, Anna
通讯作者：
Sapino, Anna
影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM
影响因子：
8
作者：
Doane, A. S.;Danso, M.;Gerald, W. L.
通讯作者：
Gerald, W. L.