Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation - Implications for the response to hormonal therapy

被引:132
作者
Mercier, Isabelle [1 ,2 ,3 ]
Casimiro, Mathew C. [1 ,2 ,3 ]
Wang, Chenguang [1 ,2 ,3 ]
Rosenberg, Anne L. [4 ]
Quong, Judy [1 ,2 ,3 ]
Minkeu, Alimatou [1 ,2 ,3 ]
Allen, Kathleen G. [4 ]
Danilo, Christiane [1 ,2 ,3 ]
Sotgia, Federica [1 ,2 ,3 ]
Bonuccelli, Gloria [1 ,2 ,3 ]
Jasmin, Jean-Francois [1 ,2 ,3 ]
Xu, Huan [6 ]
Bosco, Emily [6 ]
Aronow, Bruce [6 ]
Witkiewicz, Agnieszka [5 ]
Pestell, Richard G. [1 ,2 ,3 ]
Knudsen, Erik S. [1 ,2 ,3 ]
Lisanti, Michael P. [1 ,2 ,3 ]
机构
[1] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Dept Med Oncol, Philadelphia, PA 19107 USA
[3] Thomas Jefferson Univ, Stem Cell Biol & Regenerat Med Ctr, Philadelphia, PA 19107 USA
[4] Thomas Jefferson Univ, Dept Surg, Philadelphia, PA 19107 USA
[5] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA
[6] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA
关键词
caveolin-1; invasive breast cancer; mammary fibroblasts;
D O I
10.4161/cbt.7.8.6220
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
It is becoming increasingly apparent that the tumor micro-environment 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.
引用
收藏
页码:1212 / 1225
页数:14
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