PubMed · 9818239
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1998. Breast.. https://pubmed.ncbi.nlm.nih.gov/9818239/
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The tumor suppressor protein, p53, plays a critical role as a transcriptional activator of downstream target genes involved in the cellular response to DNA damaging agents. We examined the cell cycle checkpoint response of human mammary epithelial cells (HMEC) and their isogenic fibroblast counterparts to ionizing (IR) and ultraviolet (UV) radiation, two genotoxic agents whose DNA damage response pathways involve p53. Using flow cytometric analysis, we found that both mortal and immortalized HMEC, which contain wild-type p53 sequence, do not exhibit a G1 arrest in response to IR, but show an intact G2 checkpoint. Supportive evidence from Western analyses revealed that there was neither an increase in p53 nor one of its downstream targets, p21WAF1, in HMEC exposed to IR. In contrast, isogenic mammary fibroblasts arrest at the G1 checkpoint and induce the p53 and p21WAF1 proteins following IR. By comparison, HMEC exposed to UV displayed an S phase arrest and induced the expression of p53 and p21WAF1. Our results show that the cellular response to DNA damage depends on both the type of damage introduced into the DNA and the specific cell type.
Human breast fibroblasts have been shown to express urokinase-type plasminogen activator (uPA). This suggests that fibroblasts are actively involved in the process of uPA-directed breast tumor proteolysis. To investigate a possible role for the insulin-like growth factors (IGFs) in regulating uPA expression in human breast fibroblasts, we correlated the expression of uPA with the expression of IGF-1 and IGF-2 in a paired panel of normal and tumor tissue-derived human breast fibroblasts in vitro. Analysis of reverse transcribed polymerase chain reaction (RT-PCR) amplified mRNA revealed that the tumor-derived fibroblast strain expressed significantly more basal uPA mRNA and significantly less IGF-1 mRNA when compared to their normal counterpart. The expression of basal IGF-2 mRNA did not differ between these cultures. For both normal and tumor tissue-derived fibroblasts, cytokine- and growth factor-induced steady-state levels of uPA and IGF-1 mRNA were inversely related. No such correlation was found for uPA and IGF-2 mRNA. While exogenously added IGF-1 decreased the amount of uPA mRNA transcripts similarly in both normal and tumoral fibroblasts, exogenously added uPA decreased the amount of IGF-1 mRNA transcripts only in tumor tissue-derived fibroblasts. These data suggest that in human breast fibroblasts IGF-1 controls the expression of uPA and that, possibly due to an altered sensitivity to uPA, tumor-associated fibroblasts have escaped this local control mechanism.