Expression of p21waf1/Cip1 in stromal fibroblasts of primary breast tumors.
During carcinogenesis, stromal fibroblasts undergo certain changes in concert with their neoplastic neighbors, an interaction that progressively leads to a cancer-associated state. However, despite the increasing appreciation of the importance of stromal/tumor interactions in the progression of cancer, little is known about the factors responsible for regulating the crosstalk between stromal fibroblasts and neoplastic cells. Here we show that the stage of the disease in primary human breast lesions affects p21 expression in the fibroblasts. In stromal fibroblasts of benign fibroadenomas, p21 exhibits a periductal pattern of staining, which is abolished in malignant adenocarcinomas in which p21 immunopositivity exhibits a mosaic pattern that eventually is abolished in more aggressive types of the disease. In order to address the role of fibroblasts' p21 in tumorigenesis, we have reconstituted MCF7 human breast cancers in mice, with fibroblasts differing in the p21 status. These experiments showed that p21 deficiency in stromal fibroblasts accelerates tumor growth through cell non-autonomous mechanism(s). In addition, even a transient, siRNA-mediated p21 suppression in fibroblasts sufficiently stimulates MCF7 and MDA-MB-231 growth in vivo. We propose that p21 regulation is intimately linked with the ability of stromal cells to affect tumor growth.
Trimis
George
G
Department of Biological Chemistr, Aretaieion Hospital, University of Athens Medical School, Athens, Greece.
Chatzistamou
Ioulia
I
Politi
Katerina
K
Kiaris
Hippokratis
H
Papavassiliou
Athanasios G
AG
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D016009:Chi-Square Distribution; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering; D017154:Stromal Cells / Q000378:metabolism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D014746:Vimentin