Identification of an X-linked locus modifying mouse skin tumor susceptibility

George, Kenneth; Iacobucci, Audrey; Uitto, Jessica; O’Brien, Thomas G.

doi:10.1002/mc.20130

Cited by 12 publications

(6 citation statements)

References 19 publications

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“…From the study with Ornithine decarboxylase (Odc) transgenic BALB/cJ and C57BL/6J mice, significant linkage of the skin tumour induced by DMBA and the Odc transgene was detected in the interval between D4Mit31 and D4Mit52 (51.3–54.9 cM) [24]. These two strains may also share a common resistant allele and could be used for haplotype mapping to identify the candidate.…”

Section: Discussionmentioning

confidence: 99%

New chemically induced skin tumour susceptibility loci identified in a mouse backcross between FVB and dominant resistant PWK

et al. 2007

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Background: A variety of skin cancer susceptibility among mouse strains has allowed identification of genes responsible for skin cancer development. Fifteen Skts loci for skin tumour susceptibility have been mapped so far by using the two-stage skin carcinogenesis model [induced by 7.12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)]. A few responsible genes have been identified using wild-derived dominant resistant Mus spretus mice, and one has been confirmed as a low penetrance cancer susceptibility gene in a variety of human cancers.

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Section: Discussionmentioning

confidence: 99%

New chemically induced skin tumour susceptibility loci identified in a mouse backcross between FVB and dominant resistant PWK

et al. 2007

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“…ODC and SAMDC, key enzymes in PAs biosynthesis, are markedly overexpressed in many human cancers [13]. ODC overexpression in cell lines mimics a phenotype comparable to malignant cells like higher proliferation rate, loss of contact inhibition, and generates aggressive tumors when implanted in nude mice [14][15][16]. ODC has also been proposed as the mother target of MYC family of oncoproteins [17,18].…”

Section: Introductionmentioning

confidence: 99%

Targeting polyamine biosynthetic pathway through RNAi causes the abrogation of MCF 7 breast cancer cell line

et al. 2015

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The diamine putrescine and polyamines, spermidine (triamine) and spermine (tetraamine) are small organic polycations that play an indispensable role in key cellular processes such as the regulation of growth, differentiation, and macromolecular functions. Elevated levels of polyamines (PAs) have been shown to be one of the major factors involved in carcinogenesis. In this study, specific silencing of the expression of three genes of PA biosynthesis pathway, ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (SAMDC), and spermidine synthase (SPDSYN) was achieved using RNA interference in MCF 7 breast cancer cell line. For optimizing the effective small interfering nucleic acid (siNA), three variants of ODC siNA [siRNA, locked nucleic acid (LNA)-modified siRNA, and siHybrid (RNA and DNA hybrid)] were used and a dose- and time-dependent study was conducted. The PA biosynthetic genes were targeted individually and in combination. RNAi-mediated reduction in the expression of PA biosynthesis genes resulted in distorted cell morphology, reduced cancer cell viability, and migration characteristic. The most promising results were observed with the combined treatment of siSPDSYN and siODC with 83 % cell growth inhibition. On analyzing the messenger RNA (mRNA) expression profile of the cell cycle and apoptosis-related genes, it was observed that RNAi against PA biosynthetic genes downregulated the expression of CDK8, CCNE2, CCNH, CCNT1, CCNT2, CCNF, PCNA, CCND1, and CDK2, and upregulated the expression of E2F4, BAX, FAS, TP53, CDKN1A, BAK1, CDKN1B, ATM, GRANB, and ATR genes when compared with control-transfected cells. These results suggest that the targeting polyamine biosynthesis through RNAi approach could be a promising strategy for breast cancer therapy and might be extended for therapy of other cancers.

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“…Although there is no data in humans to suggest that some individuals may be at an elevated risk for nonmelanoma skin cancer based on the presence of ODC polymorphic variants, an area for future studies is whether chemoprevention using DFMO is more efficacious if combined with screening for ODC polymorphic variants that may be associated with greater potential for ODC induction and increased cancer risk (Guo et al, 2000). In addition, future studies using mouse strains with varying tumor responses may identify human genetic loci that modify ODC-dependent enhanced susceptibility to skin tumorigenesis George et al, 2005).…”

Section: Polyamine-based Therapy In Skin Cancermentioning

confidence: 99%

Polyamines and nonmelanoma skin cancer

Gilmour

2007

Toxicology and Applied Pharmacology

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Elevated levels of polyamines have long been associated with skin tumorigenesis. Tightly regulated metabolism of polyamines is critical for cell survival and normal skin homeostasis, and these controls are dysregulated in skin tumorigenesis. A key enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC) is upregulated in skin tumors compared to normal skin. Use of transgenic mouse models has demonstrated that polyamines play an essential role in the early promotional phase of skin tumorigenesis. The formation of skin tumors in these transgenic mice is dependent upon polyamine biosynthesis, especially putrescine, since treatment with inhibitors of ODC activity blocks the formation of skin tumors and causes the rapid regression of existing tumors. Although the mechanism by which polyamines promote skin tumorigenesis are not well understood, elevated levels of polyamines have been shown to stimulate epidermal proliferation, alter keratinocyte differentiation status, increase neovascularization, and increase synthesis of extracellular matrix proteins in a manner similar to that seen in wound healing. It is becoming increasingly apparent that elevated polyamine levels activate not only epidermal cells but also underlying stromal cells in the skin to promote the development and progression of skin tumors. The inhibition of polyamine biosynthesis has potential to be an effective chemoprevention strategy for nonmelanoma skin cancer.

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Identification of an X-linked locus modifying mouse skin tumor susceptibility

Cited by 12 publications

References 19 publications

New chemically induced skin tumour susceptibility loci identified in a mouse backcross between FVB and dominant resistant PWK

New chemically induced skin tumour susceptibility loci identified in a mouse backcross between FVB and dominant resistant PWK

Targeting polyamine biosynthetic pathway through RNAi causes the abrogation of MCF 7 breast cancer cell line

Polyamines and nonmelanoma skin cancer

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