title: Ionizing radiation-mediated premature senescence and paracrine interactions with cancer cells enhance the expression of syndecan 1 in human breast stromal fibroblasts: the role of TGF-β.
abstract: The cell surface proteoglycan syndecan 1 (SDC1) is overexpressed in the malignant breast stromal fibroblasts, creating a favorable milieu for tumor cell growth. In the present study, we found that ionizing radiation, a well-established treatment in human breast cancer, provokes premature senescence of human breast stromal fibroblasts in vitro, as well as in the breast tissue in vivo. These senescent cells were found to overexpress SDC1 both in vitro and in vivo. By using a series of specific inhibitors and siRNA approaches, we showed that this SDC1 overexpression in senescent cells is the result of an autocrine action of Transforming Growth Factor-β (TGF-β) through the Smad pathway and the transcription factor Sp1, while the classical senescence pathways of p53 or p38 MAPK - NF-kB are not involved. In addition, the highly invasive human breast cancer cells MDA-MB-231 (in contrast to the low-invasive MCF-7) can also enhance SDC1 expression, both in early-passage and senescent fibroblasts via a paracrine action of TGF-β. The above suggest that radiation-mediated premature senescence and invasive tumor cells, alone or in combination, enhance SDC1 expression in breast stromal fibroblasts, a poor prognostic factor for cancer growth, and that TGF-β plays a crucial role in this process.
authors.affiliation: Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Liakou
authors.affiliation: Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Mavrogonatou
authors.affiliation: Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece.
authors.forename: Harris
authors.initials: H
authors.lastname: Pratsinis
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Sophia
authors.initials: S
authors.lastname: Rizou
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Evangelou
authors.affiliation: Department of Plastic Surgery and Burns Unit, KAT General Hospital of Athens, Athens, Greece.
authors.forename: Petros N
authors.initials: PN
authors.lastname: Panagiotou
authors.affiliation: Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece.
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.|Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.|Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
authors.affiliation: Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kletsas
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology* / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000528:radiation effects; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; C508241:SDC1 protein, human; D051785:Smad Proteins; D053668:Syndecan-1; D016212:Transforming Growth Factor beta
keywords: TGF-β; breast stroma; cancer; ionizing radiation; senescence; syndecan 1