Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy.
Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy.
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DOI：
10.4161/cbt.7.8.6220
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发表时间：
2008-08
影响因子：
3.6
通讯作者：
Lisanti MP
中科院分区：
文献类型：
--
作者：
Mercier I;Casimiro MC;Wang C;Rosenberg AL;Quong J;Minkeu A;Allen KG;Danilo C;Sotgia F;Bonuccelli G;Jasmin JF;Xu H;Bosco E;Aronow B;Witkiewicz A;Pestell RG;Knudsen ES;Lisanti MP
越来越明显的是，肿瘤微环境在人类乳腺癌的发生和发展中起着至关重要的作用。因此，我们从人乳腺癌病变中分离出癌症相关成纤维细胞（CAFs），并与从同一患者中分离出的正常乳腺成纤维细胞（NFs）进行比较，研究其特性。在这里，我们证明了11个CAFs中的8个显示出小窝蛋白-1（Cav-1）蛋白表达的显著下调; Cav-1是一个公认的标志物，在成纤维细胞的致癌转化过程中通常会降低。接下来，我们进行了基因表达谱研究（DNA微阵列），并建立了CAF基因表达特征。有趣的是，与CAF相关的表达特征包括大量通过RB途径调节的基因。CAF基因特征也预测了用他莫昔芬单药治疗的乳腺癌患者的不良临床结果，表明CAF可用于预测对激素治疗的反应。最后，我们表明，替换CAFs中的Cav-1表达（使用细胞渗透性肽方法）足以逆转其过度增殖表型并防止RB过度磷酸化。总之，这些研究强调了Cav-1下调在维持人乳腺癌相关成纤维细胞异常表型中的关键作用。
It is becoming increasingly apparent that the tumor microenvironment plays a critical role in human breast cancer onset and progression. Therefore, we isolated cancer-associated fibroblasts (CAFs) from human breast cancer lesions and studied their properties, as compared with normal mammary fibroblasts (NFs) isolated from the same patient. Here, we demonstrate that 8 out of 11 CAFs show dramatic downregulation of caveolin-1 (Cav-1) protein expression; Cav-1 is a well-established marker that is normally decreased during the oncogenic transformation of fibroblasts. Next, we performed gene expression profiling studies (DNA microarray) and established a CAF gene expression signature. Interestingly, the expression signature associated with CAFs encompasses a large number of genes that are regulated via the RB-pathway. The CAF gene signature is also predictive of poor clinical outcome in breast cancer patients that were treated with tamoxifen mono-therapy, indicating that CAFs may be useful for predicting the response to hormonal therapy. Finally, we show that replacement of Cav-1 expression in CAFs (using a cell-permeable peptide approach) is sufficient to revert their hyper-proliferative phenotype and prevent RB hyper-phosphorylation. Taken together, these studies highlight the critical role of Cav-1 downregulation in maintaining the abnormal phenotype of human breast cancer-associated fibroblasts.
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影响因子：
11.2
作者：
Deeb, Kristin K.;Michalowska, Aleksandra M.;Green, Jeffrey E.
通讯作者：
Green, Jeffrey E.
影响因子：
15.9
作者：
Bosco, Emily E.;Wang, Ying;Knudsen, Erik S.
通讯作者：
Knudsen, Erik S.
影响因子：
11.2
作者：
Hwang, Rosa F.;Moore, Todd;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.
影响因子：
82.9
作者：
Bucci, M;Gratton, JP;Sessa, WC
通讯作者：
Sessa, WC
影响因子：
37.8
作者：
Jasmin, Jean-Francois;Mercier, Isabelle;Lisanti, Michael P.
通讯作者：
Lisanti, Michael P.