Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy.
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.
Mercier
Isabelle
I
Kimmel Cancer Center, Department of Cancer Biology and Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Casimiro
Mathew C
MC
Wang
Chenguang
C
Rosenberg
Anne L
AL
Quong
Judy
J
Minkeu
Alimatou
A
Allen
Kathleen G
KG
Danilo
Christiane
C
Sotgia
Federica
F
Bonuccelli
Gloria
G
Jasmin
Jean-François
JF
Xu
Huan
H
Bosco
Emily
E
Aronow
Bruce
B
Witkiewicz
Agnieszka
A
Pestell
Richard G
RG
Knudsen
Erik S
ES
Lisanti
Michael P
MP
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051242:Caveolin 1 / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008957:Models, Genetic; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism
D051242:Caveolin 1; D016160:Retinoblastoma Protein