Our data unequivocally identify CPDs as the principal cause of nonmelanoma skin cancer and provide genetic evidence that CPD-photolyase enzymes can be employed as effective tools to combat skin cancer.
High levels of the p53 protein are immunohistochemically detectable in a majority of human nonmelanoma skin cancers and UVB-induced murine skin tumors. These increased protein levels are often associated with mutations in the conserved domains of the p53 gene. To investigate the timing of the p53 alterations in the process of UVB carcinogenesis, we used a well defined murine model (SKH:HR1 hairless mice) in (1), and from animal studies it appeared that the UVB part of the solar spectrum is the most carcinogenic (2). This has been substantiated by detection of mutations in the p53 tumor-suppressor gene in human SCCs (3) and basal cell carcinomas (4) that are characteristic for UVB radiation: i.e., mainly C T transitions at dipyrimidine sites among which are CC TT tandem mutations. There are indications that p53 is involved in the earliest stages of human nonmelanoma skin cancer. Recently, it has been reported that p53 mutations are already present in a benign precursor of SCC, actinic keratosis (5), and in skin adjacent to basal cell carcinomas (6). Furthermore, it has been shown that CC --TT tandem mutations in the p53 gene are detectable in biopsies from nonneoplastic skin of sun-exposed sites from Australian skin cancer patients (7).The suspected causal relationship between chronic UV exposure and p53 mutation and their relation to tumor forThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. mation can most directly and unequivocally be established in an animal model in which UV exposure is the only well controlled carcinogenic agent. A robust model is the SKH:HR1 hairless mouse for which the relationship between UVB exposure and carcinogenic response is well established (8, 9) and for which the pathogenesis of UVB-induced SCC shows close similarities with that of human SCC (10).Under physiological circumstances, the wild-type p53 protein has a very short half-life and is present in such small quantities that it is not immunohistochemically detectable (11,12). There are different pathways that lead to accumulation of the p53 protein up to immunohistochemically detectable levels. (i) DNA damage gives rise to a temporary accumulation of the wild-type p53 protein resulting in an arrest of the cell cycle assumed to prevent replication of damaged DNA (13). (ii) Missense mutations in the p53 gene in general lead to a dramatic increase in half-life of the p53 protein (11). In contrast to the transient accumulation of wild-type p53, the latter can lead to a constitutively high p53 level in the cell. We have recently reported that >75% of UVB-induced murine skin carcinomas show immunostaining with the p53-specific polyclonal antiserum CM-5, which was primarily confined to the proliferative compartments of the tumors. A substantial part of the p53-positive staining was associated with point mutations in the conserved domains of the p53 gene (14). Subsequ...
Organoid technology has revolutionized the study of human organ development, disease and therapy response tailored to the individual. Although detailed protocols are available for the generation and long-term propagation of human organoids from various organs, such methods are lacking for breast tissue. Here we provide an optimized, highly versatile protocol for long-term culture of organoids derived from either normal human breast tissues or breast cancer (BC) tissues, as well as culturing conditions for a panel of 45 biobanked samples, including BC organoids covering all major disease subtypes (triple-negative, estrogen receptor-positive/progesterone Reprints and permissions information is available at www.nature.com/reprints.
Clusters of p53 immunopositive epidermal keratinocytes (so-called p53 patches, clones or foci) are found in sun or ultraviolet (UV) light-exposed skin. We investigated to what extent these p53 patches are genuine precursors of skin carcinomas in chronically irradiated hairless (SKH1) mice. The mutation spectra of exons 5-8 of the p53 gene of laser-micro-dissected mutant p53 patches and carcinomas were therefore compared. The mutations we found were mainly UV-signature mutations (C-->T and CC-->TT at dipyrimidine sites) located at known hotspots. No significant differences were found between both spectra, indicating that all p53 patches harbour mutations with which they could progress to carcinomas. To examine whether these p53 patches can be used as tumour risk indicators, we made an extensive comparison of the induction kinetics of these patches and carcinomas in genetically modified mice with various defects in nucleotide excision repair (NER), i.e. xeroderma pigmentosum A (Xpa), Xpc and Cockayne syndrome B (Csb) and wild-type mice. In this aforementioned order, the mouse strains developed both p53 patches and carcinomas in the course of daily exposure to 40 J/m(2) UV. Hence, the order in which the NER-deficient mice developed patches was predictive of the order in which they developed tumours. The induction kinetics of the patches in Xpc-deficient mice differed notably from the others: there was a stationary phase (days 13-41) where the numbers were limited to 5-10 patches per mouse before an explosive increase which ran parallel to the other groups. The chance that a p53 patch progresses to carcinoma is relatively small (estimated at 1 out of 8300-40,000/individual when the first tumour appears), but our results are strongly indicative of a causal relationship between p53 patches and carcinomas.
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