共 44 条
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.
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页码:1212 / 1225
页数:14
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