cyclin-d1 and Carcinoma--Basal-Cell

To better understand the influence of ultraviolet (UV) irradiation on the initial steps of skin carcinogenesis, we examine patches of labeled keratinocytes as a proxy for clones in the interfollicular epidermis (IFE) and measure their size variation upon UVB irradiation. Multicolor lineage tracing reveals that in chronically irradiated skin, patches near hair follicles (HFs) increase in size, whereas those far from follicles do not change. This is explained by proliferation of basal epidermal cells within 60 μm of HF openings. Upon interruption of UVB, patch size near HFs regresses significantly. These anatomical differences in proliferative behavior have significant consequences for the cell of origin of basal cell carcinomas (BCCs). Indeed, a UV-inducible murine BCC model shows that BCC patches are more frequent, larger, and more invasive near HFs. These findings have major implications for the prevention of field cancerization in the epidermis.

Topics: Animals; Carcinoma, Basal Cell; Cell Proliferation; Cyclin D1; Disease Models, Animal; Epidermis; Hair Follicle; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms, Radiation-Induced; Skin Neoplasms; Stem Cells; Tumor Suppressor Protein p53; Ultraviolet Rays

Around 80% of nonmelanoma skin cancers (NMSCs) are basal cell carcinoma (BCC), still studies evaluating the efficacy of chemopreventive agents during early stage/s of BCC development are lacking. Accordingly, utilizing the well-established patched (Ptch)+/- mouse model of ultraviolet B (UVB) radiation-induced BCC formation, we excised skin samples from UVB exposed Ptch+/- and Ptch+/+ mice before tumor formation to study the promotion/progression of BCC and to determine the efficacy and target/s of silibinin, a well-known skin cancer chemopreventive agent. UVB exposure for 1 month increased the number of mast cells in Ptch+/- mice by ~48% (P < 0.05), which was completely inhibited by silibinin. Polymerase chain reaction profiler array analysis of skin samples showed strong molecular differences between Ptch+/+ and Ptch+/- mice which were either unexposed or UVB irradiated+/- silibinin treatment. Most notably, silibinin treatment significant decreased the expression of BMP-2, Bbc3, PUMA, and Ccnd1 in Ptch+/- mice irradiated with silibinin + UVB. Additional studies showed that silibinin targets UVB-induced expression of bone morphogenetic protein 2 (BMP-2) in Ptch+/- mouse skin. Last, our studies found that silibinin strongly attenuates UVB-induced BMP-2 expression and DNA damage in Ptch+/- mouse skin ex vivo only after single UVB exposure. Together, our results suggest a possible role of mast cell recruitment and BMP-2 activation in the early stages of BCC development; these are strongly inhibited by silibinin suggesting its possible chemopreventive efficacy against BCC formation in long-term UVB exposure regimen.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis Regulatory Proteins; Bone Morphogenetic Protein 2; Carcinoma, Basal Cell; Chemoprevention; Cyclin D1; Disease Models, Animal; DNA Damage; Mast Cells; Mice; Mice, Transgenic; Patched-1 Receptor; Signal Transduction; Silybin; Skin; Skin Neoplasms; Tumor Suppressor Proteins; Ultraviolet Rays

Thyroid hormones (THs) mediate pleiotropic cellular processes involved in metabolism, cellular proliferation, and differentiation. The intracellular hormonal environment can be tailored by the type 1 and 2 deiodinase enzymes D2 and D3, which catalyze TH activation and inactivation respectively. In many cellular systems, THs exert well-documented stimulatory or inhibitory effects on cell proliferation; however, the molecular mechanisms by which they control rates of cell cycle progression have not yet been entirely clarified. We previously showed that D3 depletion or TH treatment influences the proliferation and survival of basal cell carcinoma (BCC) cells. Surprisingly, we also found that BCC cells express not only sustained levels of D3 but also robust levels of D2. The aim of the present study was to dissect the contribution of D2 to TH metabolism in the BCC context, and to identify the molecular changes associated with cell proliferation and survival induced by TH and mediated by D2 and D3.. We used the CRISPR/Cas9 technology to genetically deplete D2 and D3 in BCC cells and studied the consequences of depletion on cell cycle progression and on cell death. Cell cycle progression was analyzed by fluorescence activated cell sorting analysis of synchronized cells, and the apoptosis rate by annexin V incorporation.. Mechanistic investigations revealed that D2 inactivation accelerates cell cycle progression thereby enhancing the proportion of S-phase cells and cyclin D1 expression. Conversely, D3 mutagenesis drastically suppressed cell proliferation and enhanced apoptosis of BCC cells. Furthermore, the basal apoptotic rate was oppositely regulated in D2- and D3-depleted cells.. Our results indicate that BCC cells constitute an example in which the TH signal is finely tuned by the concerted expression of opposite-acting deiodinases. The dual regulation of D2 and D3 expression plays a critical role in cell cycle progression and cell death by influencing cyclin D1-mediated entry into the G1-S phase. These findings reinforce the concept that TH is a potential therapeutic target in human BCC.

Topics: Animals; Apoptosis; Carcinoma, Basal Cell; Cell Cycle; Cell Death; Cell Survival; CRISPR-Cas Systems; Cyclin D1; Flow Cytometry; G1 Phase Cell Cycle Checkpoints; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Mice; Mice, Transgenic; Mutagenesis, Site-Directed; Skin Neoplasms; Thyroid Hormones

PC cell-derived growth factor (PCDGF) is an autocrine growth factor originally purified from the highly tumorigenic teratoma PC cell line. It participates in tumorigenesis and tumour progression through upregulation of cyclin D1. To date, there has been no report on the role of PCDGF in skin cancer, to our knowledge.. To investigate the expression of PCDGF and cyclin D1 in basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and seborrhoeic keratosis (SK), and their relationship with the clinicopathological parameters of SCC.. Immunohistochemical expression of PCDGF and cyclin D1 was examined in 42 SCC, 30 BCC and 20 SK tissues.. PCDGF and cyclin D1 were overexpressed in SCC or BCC tissues compared with normal skin or SK, and their expressions were significantly higher in SCC than in BCC. Moreover, positive expression of PCDGF and cyclin D1 was significantly correlated with depth of invasion and metastasis of SCC. There was significant correlation between PCDGF and cyclin D1 expression in SCC.. Expression of PCDGF and cyclin D1 plays an important role in the tumorigenesis of BCC and SCC. Abnormal expression of PCDGF and Cyclin D1 may be related to invasion and metastasis of SCC.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cyclin D1; Female; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Keratosis, Seborrheic; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Proteins; Progranulins; Skin; Skin Neoplasms

Activation of the Hedgehog (Hh) pathway is known to drive development of basal cell carcinoma and medulloblastomas and to associate with many other types of cancer, but the exact molecular mechanisms underlying the carcinogenesis process remain elusive. We discovered that skin tumors derived from epidermal expression of oncogenic Smo, SmoM2, have elevated levels of IL-11, IL-11Rα, and STAT3 phosphorylation at Tyr(705). The relevance of our data to human conditions was reflected by the fact that all human basal cell carcinomas examined have detectable STAT3 phosphorylation, mostly in keratinocytes. The functional relevance of STAT3 in Smo-mediated carcinogenesis was revealed by epidermal specific knockout of STAT3. We showed that removal of STAT3 from mouse epidermis dramatically reduced SmoM2-mediated cell proliferation, leading to a significant decrease in epidermal thickness and tumor development. We also observed a significant reduction of epidermal stem/progenitor cell population and cyclin D1 expression in mice with epidermis-specific knockout of STAT3. Our evidence indicates that STAT3 signaling activation may be mediated by the IL-11/IL-11Rα signaling axis. We showed that tumor development was reduced after induced expression of SmoM2 in IL-11Rα null mice. Similarly, neutralizing antibodies for IL-11 reduced the tumor size. In two Hh-responsive cell lines, ES14 and C3H10T1/2, we found that addition of Smo agonist purmorphamine is sufficient to induce STAT3 phosphorylation at Tyr(705), but this effect was abolished after IL-11Rα down-regulation by shRNAs. Taken together, our results support an important role of the IL-11Rα/STAT3 signaling axis for Hh signaling-mediated signaling and carcinogenesis.

Topics: Animals; Blotting, Western; Carcinoma, Basal Cell; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Cyclin D1; Epidermal Cells; Epidermis; Female; Humans; Immunohistochemistry; Interleukin-11 Receptor alpha Subunit; Male; Mice; Mice, Knockout; Mice, Transgenic; Morpholines; Phosphorylation; Purines; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Skin Neoplasms; Smoothened Receptor; STAT3 Transcription Factor

Pilomatrix carcinoma, a malignant counterpart of pilomatrixoma, is a rare skin neoplasm composed of basaloid and shadow cells that characterize differentiation toward the hair matrix. The authors present a case of pilomatrix carcinoma of the clitoris, a very unusual location not previously reported. Diagnostic criteria and differential diagnoses are discussed. Pilomatrix carcinoma should be differentiated from benign pilomatrixoma and other carcinomas with shadow cells, including basal cell carcinoma with matrical differentiation and metastases of visceral carcinomas with shadow cells.

Topics: beta Catenin; Biomarkers, Tumor; Carcinoma, Basal Cell; Cell Nucleus; Clitoris; Cyclin D1; Diagnosis, Differential; Fatal Outcome; Female; Hair Diseases; Humans; Pilomatrixoma; Skin Neoplasms; Vulvar Neoplasms

Basal cell carcinoma is a very common malignant skin tumor that rarely metastasizes but is often locally aggressive. In a number of studies conducted by different investigators, Bcl2, beta-catenin, cyclin D1, hMSH2, and alpha-smooth muscle actin have been reported to have potential for predicting basal cell carcinoma aggressiveness. However, these reports were inconclusive and sometimes contradictory. We therefore studied the expression and topographic locations (tumor versus stroma) of all these gene products in a group of clinically proven aggressive basal cell carcinomas (n = 30) and randomly selected control cases of nonaggressive basal cell carcinomas (n = 33). The results were subjected to statistical analysis with Mann-Whitney test and logistic regression. The accuracy of the resulting significant discriminating criteria was further tested using the omnibus tests of model coefficients. With multivariate analysis, differential expression of Bcl-2, beta-catenin, and cyclin D1 was not significantly different between aggressive and nonaggressive tumors. hMSH2 expression was up-regulated in the aggressive tumors (P = .005). Alpha-smooth muscle actin was expressed by tumor cells in both study groups, but stromal expression of alpha-smooth muscle actin was restricted to the aggressive tumors and highly predictive of aggressive behavior (P < .001; accuracy, 87%). Logistic regression combining the expression of alpha-smooth muscle actin and hMSH2 yielded a predictive model with 97% accuracy (P < .001). These data show conclusively that aggressive basal cell carcinomas express alpha-smooth muscle actin in the stroma, whereas nonaggressive basal cell carcinomas express alpha-smooth muscle actin in the tumor cells, and that stromal expression of alpha-smooth muscle actin is an accurate, reliable, and easy to use marker of aggressiveness in basal cell carcinomas and can be used in clinical practice for surgical therapeutic decisions.

Topics: Actins; beta Catenin; Biomarkers, Tumor; Carcinoma, Basal Cell; Cyclin D1; Humans; Logistic Models; Muscle, Smooth; MutS Homolog 2 Protein; Neoplasm Recurrence, Local; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; Stromal Cells

Patched1 heterozygous mice (Ptch1(+/-)) are useful for basal cell carcinoma (BCC) studies, being remarkably susceptible to BCC induction by ultraviolet or ionizing radiation. Analogously, skin carcinogenesis-susceptible (Car-S) mice are elective for studies of papilloma and squamous cell carcinoma (SCC) induction. We previously reported a striking effect of gender on BCC induction in Ptch1(+/-) mice, with total resistance of females; likewise, Car-S females show increased skin tumor resistance relative to males. Here, we investigated the protective role of endogenous estrogen in skin keratinocyte tumorigenesis. Control (CN) and ovariectomized Ptch1(+/-) or Car-S females were irradiated for BCC induction or topically treated with chemical carcinogens for SCC induction. Susceptibility to BCC or SCC was dramatically increased in ovariectomized Ptch1(+/-) and Car-S females and restored to levels observed in males. Remarkably, progression of initially benign papillomas to malignant SCC occurred only in ovariectomized Car-S females. We explored the mechanisms underlying tumor progression and report overexpression of estrogen receptor (ER)-alpha, downregulation of ERbeta and upregulation of cyclin D1 in papillomas from ovariectomized Car-S relative to papillomas from CN females. Thus, an imbalanced ERalpha/ERbeta expression may be associated with estrogen-mediated modulation of non-melanoma skin carcinogenesis, with a key role played by cyclin D1. Our findings underscore a highly protective role of endogenous estrogen against skin tumorigenesis by diverse agents in two independent mouse models of skin cancer.

Topics: Animals; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Cyclin D1; Disease Models, Animal; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Male; Mice; Neoplasms, Radiation-Induced; Ovariectomy; Papilloma; Patched Receptors; Patched-1 Receptor; Receptors, Cell Surface; Skin Neoplasms; Ultraviolet Rays

We planned this study to analyze probable associations between p53, cyclinD1, Ki67 and histopathological features in basal cell carcinomas (BCC).. Histological differentiation types, histological growth patterns and tissue responses were analyzed in 50 cases of BCC. In immunohistochemical analysis, p53, cyclinD1 and Ki67 antibodies were investigated. P53 expression was evaluated based on a cut-off value of 25% positivity. CyclinD1 expression was graded from 0 to 3+ according to the percentage of positive nuclear staining. The percentage of positively staining cells for Ki67 was recorded.. The following significant correlations were detected. Solid infiltrative type differentiation was related to the infiltrative histological growth pattern. The rates of p53 positivity and severe fibrosis in the groups of mixed and infiltrative growth patterns were higher than others. Besides, p53-positive cases showed more severe fibrosis and had a higher mean value for Ki67 index. Epidermal p53 and cyclinD1 clones in normal epidermal areas adjacent to tumors were noticed in 42% and 52% of the cases, respectively.. P53 expression seems to be related to Ki67 index and some histopathological features of BCC, such as infiltrative histological growth pattern and probably fibrosis.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Basal Cell; Cyclin D1; Female; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Skin Neoplasms; Tumor Suppressor Protein p53

Mutations in the Hedgehog receptor, Patched 1 (Ptch1), have been linked to both familial and sporadic forms of basal cell carcinoma (BCC), leading to the hypothesis that loss of Ptch1 function is sufficient for tumor progression. By combining conditional knockout technology with the inducible activity of the Keratin6 promoter, we provide in vivo evidence that loss of Ptch1 function from the basal cell population of mouse skin is sufficient to induce rapid skin tumor formation, reminiscent of human BCC. Elimination of Ptch1 does not promote the nuclear translocation of beta-catenin and does not induce ectopic activation or expression of Notch pathway constituents. In the absence of Ptch1, however, a large proportion of basal cells exhibit nuclear accumulation of the cell cycle regulators cyclin D1 and B1. Collectively, our data suggest that Ptch1 likely functions as a tumor suppressor by inhibiting G1-S phase and G2-M phase cell cycle progression, and the rapid onset of tumor progression clearly indicates Ptch1 functions as a "gatekeeper." In addition, we note the high frequency and rapid onset of tumors in this mouse model makes it an ideal system for testing therapeutic strategies, such as Patched pathway inhibitors.

Topics: Animals; beta Catenin; Carcinoma, Basal Cell; Cell Cycle; Cell Nucleus; Cell Transformation, Neoplastic; Cyclin B; Cyclin B1; Cyclin D1; Hair Follicle; Mice; Mice, Transgenic; Patched Receptors; Patched-1 Receptor; Receptors, Cell Surface; Receptors, Notch; Skin; Skin Neoplasms

Topics: Adult; Apoptosis; Biopsy, Needle; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Case-Control Studies; Caspases; Cell Cycle; Confidence Intervals; Cyclin D1; Female; Gene Expression Regulation, Neoplastic; Genetic Variation; Humans; Incidence; Melanoma; Middle Aged; Multivariate Analysis; Odds Ratio; Polymorphism, Genetic; Probability; Prognosis; Reference Values; Risk Assessment; Sensitivity and Specificity; Skin Neoplasms

Deregulation of the cell-cycle G1-restriction point control via abnormalities of Rb-pathway components is a frequent event in the formation of cancer. The aim of this study was to evaluate numerical aberrations of the Cyclin D1 (CCND1, PRAD1, bcl-1) gene locus at chromosome 11q13 in basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin and to compare it with the Cyclin D1 protein expression. Fluorescence in situ hybridization with DNA-probes specific for the Cyclin D1 gene locus and the centromere of chromosome 11 as well as immunostaining for Cyclin D1 protein was applied on 5 microm serial paraffin sections. Six of the 30 (20%) SCCs showed additional Cyclin D1 gene copies and 2/30 (6.6%) cases had a loss of the Cyclin D1 gene locus in relation to the centromere 11 number. In contrast, only one of the 14 BCCs (7%) showed one additional Cyclin D1 gene copy in relation to the centromere 11 number. None of the BCCs demonstrated aneusomy for chromosome 11 in contrast to SCCs, where it was found in 21/30 (70%) cases. Twenty-six of the 30 (86.6%) cutaneous SCCs and 13/14 (93%) BCCs expressed Cyclin D1 protein. All SCCs and the BCC with additional Cyclin D1 gene copies showed positivity for Cyclin D1 protein. Both SCCs with less Cyclin D1 gene copies than centromere 11 signals showed a weak protein expression. Our findings suggest that numerical abnormalities of the Cyclin D1 gene locus could result in an altered gene-dose effect, possibly leading to an aberrant expression in affected tumor cells. This might result in deregulation of cell cycle control, eventually leading to uncontrolled cell cycle progression.

Topics: Aged; Aneuploidy; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Chromosomes, Human, Pair 11; Cyclin D1; Female; Humans; In Situ Hybridization, Fluorescence; Male; Middle Aged; Skin Neoplasms

Pyrosequencing is a new method to detect single nucleotide polymorphisms (SNPs). Basal cell carcinoma (BCC) is one of the most common neoplasms in the world, and its incidence has been increasing worldwide in recent years. BCC is caused by an interplay between genetic and environment factors.. Pyrosequencing and restrict fragment length polymorphism (RFLP) were used in the study. We conducted a case-control association study in BCC cases and controls from Sweden. For SNPs in IL-6, IL-10 and IL-1beta, 241 cases were at the age of 27-70 years (mean 50 years) and 260 healthy controls were 26-71 years (mean 48 years), 241 cases were 27-70 years (mean 50 years) and 574 healthy controls were 22-74 years (mean 52 years) for cyclin D1 G870A, 197 cases were 29-69 years (mean 47 years) and 574 healthy controls were 22-74 years (mean 52 years) for MTHFR C677T and A1298C. Nine SNPs for IL-6-174G/C, -634G/C and -597G/A; IL-10-1082G/A and -592C/A; IL-1beta-511C/T; cyclin D1 G870A; MTHFR C677T and A1298C were analyzed.. Most genotype distributions were in accordance with Hardy-Weinberg equilibrium (HWE), except IL-10-1082G/A, which had a significantly deviation from HWE in BCC cases (P<0.05). Linkage disequilibrium was observed between the -174 and -597 alleles in the IL-6 gene in the studied populations. The differences for cyclin D1 G870A and methylenetetrahydrofolate reductase (MTHFR) C677T were found between BCC cases group and control group (P<0.05, OR=1.34, 95% CI, 1.00-1.74; P<0.05, OR=1.67, 95% CI, 1.13-2.47, respectively).. Cyclin D1 G870A and MTHFR C677T were associated with BC cases from Sweden, the other SNPs studied here were not associated with BCC, but chance cannot be excluded.

Topics: Adult; Aged; Carcinoma, Basal Cell; Cohort Studies; Cyclin D1; DNA Primers; Female; Humans; Interleukin-1; Interleukin-10; Interleukin-6; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Sensitivity and Specificity; Sequence Analysis, DNA; Skin Neoplasms

Virtually all BCCs have deregulation of the Hedgehog (Hh) signalling pathway and a proportion show nuclear beta-catenin accumulation. The latter is thought to be due to Hh pathway-directed Wnt expression but this has not been tested. An alternative cause of nuclear beta-catenin accumulation is gene mutation, which stabilizes the protein. Theoretically, reduced E-cadherin expression could also be important because it can sequester beta-catenin at the cell membrane. In turn, nuclear beta-catenin can increase expression of MYC and cyclin D1, thus potentially altering proliferation.. To assess whether nuclear beta-catenin occurs in BCC, and to look at potential causes and consequences.. Nuclear beta-catenin was assessed by immunohistochemistry, and its causes by analysis of E-cadherin expression, beta-catenin exon 3 mutation and WNT5A expression. Its consequences were assessed by analysing proliferation.. We found nuclear beta-catenin in 20 of 86 paraffin-embedded sections of BCCs using immunohistochemistry. BCCs showed increased WNT5A relative to the surrounding skin. No mutations in exon 3 of the beta-catenin gene were found in 10 cases. There was no association between beta-catenin localization and E-cadherin expression. Tumours with nuclear beta-catenin had significantly higher proliferation (P < 0.01).. The absence of beta-catenin gene mutations indicate that the Hh pathway-directed Wnt signalling remains the most likely cause of nuclear beta-catenin accumulation in BCC. Additionally, the correlation with increased proliferation is the first evidence that nuclear beta-catenin may have a biological effect. However, a causal link between Hh pathway deregulation, Wnt ligand overexpression, nuclear beta-catenin accumulation and increased proliferation remains to be confirmed.

Topics: Aged; beta Catenin; Biomarkers, Tumor; Cadherins; Carcinoma, Basal Cell; Cell Division; Cell Nucleus; Chi-Square Distribution; Cyclin D1; Cytoskeletal Proteins; Female; Gene Expression; Genes, myc; Humans; Immunohistochemistry; Male; Middle Aged; Proto-Oncogene Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin Neoplasms; Trans-Activators; Wnt Proteins; Wnt-5a Protein

Basal cell carcinomas (BCCs) may be subdivided into primary with a favorable biologic course (BCC1) and recurrent and/or metastatic (BCC2). No clear association between primary tumor location, histologic subtype, or other clinicopathologic variables and predisposition for BCC2 has been found. Histopathologic criteria are limited for prognostication. To identify prognostic factors useful for planning therapy, we studied cyclin D1 immunohistochemical expression, DNA ploidy, and epiluminescence light microscopic (ELM) patterns in 60 cases of BCC (30 BCC1 and 30 BCC2) in the head and neck region, half of which were hyperpigmented. Cyclin D1 was absent in 27 cases, expressed at low level in 4 cases, and overexpressed in 30 cases. Seven BCCs were euploid, 28 exhibited a mixed cellular population, and 25 were aneuploid. Among aneuploid tumors, hypodiploidy was found in 12. Among the 30 pigmented carcinomas, only 15 showed a typical ELM pattern. No association between pigmentation and more aggressive biologic behavior of BCC was found. These results and follow-up data seem to indicate that an unfavorable outcome can be predicted by hyperexpression of cyclin D1, aneuploidy, and an atypical ELM pattern for pigmented cases. A definite hypodiploid peak was associated with worse prognosis. The analysis of cyclin D1 expression and DNA ploidy may help identify BCC with an aggressive phenotype and a poor clinical outcome.

Topics: Carcinoma, Basal Cell; Cyclin D1; DNA, Neoplasm; Follow-Up Studies; Head and Neck Neoplasms; Humans; Immunohistochemistry; Luminescent Measurements; Microscopy; Ploidies; Prognosis; Skin Neoplasms; Skin Pigmentation

Although the overexpression of cyclin D1 has been believed to play important roles in neoplastic transformation of some tumors, little is known about the function of cyclin D1 protein in carcinogenesis in human skin. A total of 307 patients with nonmelanocytic skin cancer, being 46 with Bowen's disease (BOD), 134 with squamous cell carcinoma (SCC) and 127 with basal cell carcinoma (BCC), were investigated immunohistochemically using monoclonal antibody to cyclin D1 by the LSAB method, to assess the expression of cyclin D1 in skin cancer including its precursors. The positive rates of cyclin D1 immunostaining in BOD, SCC and BCC were 63.0%, 69.4% and 54.3%, respectively. The positive rates in dysplasia adjoining BOD, SCC and BCC were 43.6%, 67.9% and 59.8%, respectively. In morphologically normal skin, however, only 2 cases, 1 of SCC and 1 of BCC, exhibited positive staining. These findings suggested that overexpression of cyclin D1 is an early event in dysplastic lesions of skin. Overexpression of cyclin D1 was related to sun exposure, especially in dysplasia of SCC. The score for cyclin D1 expression in dysplasia of BCC was correlated with age. Expression of cyclin D1 markedly increased from normal skin through dysplasia to BOD, but was not significantly related to the degree of SCC differentiation. These findings demonstrate that the effect of cyclin D1 overexpression is restricted to proliferation of cells, so that they gain a growth advantage, but their differentiation is not increased. Comparison with the results for p53 protein expression in these tumors, a significant correlation with cyclin D1 expression was found in dysplasia in BOD and SCC, and in patients with BCC who were less than 74 years old. These findings suggested the hypothesis that prior aberrant p53 expression may affect or regulate the overexpression of cyclin D1.

Topics: Adult; Aged; Aged, 80 and over; Aging; Bowen's Disease; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cyclin D1; Female; Humans; Immunohistochemistry; Male; Middle Aged; Skin Neoplasms; Staining and Labeling; Sunlight

We previously described associations between basal cell carcinoma (BCC) numbers and allelic variants at loci that mediate host response to ultraviolet radiation (UV). These associations were largely exerted in cases with the multiple presentation phenotype (MPP). This phenotype describes patients who present at their first or a later presentation with a cluster of BCC (2-10 new BCC). Remaining BCC cases have the single presentation phenotype (SPP) and may develop more than one BCC but only have single new lesions at any presentation. We proposed that the MPP cases comprise a high-risk group as they suffer significantly more lesions than SPP cases. We are attempting to determine, in the total BCC case group and subgroups, how many genes influence BCC numbers and their relative importance. In this study, we assessed the influence of two further candidates, glutathione S-transferase GSTP1 and cyclin D1 (CCND1), on tumour numbers in a total group of 457 patients comprising MPP and SPP cases. The relative importance of these genes in comparison with occupational UV exposure and host response (skin type) was also considered. We found that the frequencies of GSTP1 genotypes based on the Ile105 and Val105-expressing alleles and CCND1 AA, AG, GG genotypes were similar in MPP and SPP cases and that there were no significant associations between GSTP1 or CCND1 genotypes and BCC numbers in the total or SPP groups. However, in the MPP cases, GSTP1 Val105/Val105 was associated with more tumours (P = 0.05, reference GSTP1 Ile105/Ile105). Inclusion of skin type and indoor/outdoor occupation in the negative binomial regression models did not alter the associations of these genotypes with tumour numbers. DNA from 258 cases was analysed to identify GSTP1*A (Ile105-Ala114), GSTP1*B (Val105-Ala114), GSTP1*C (Val105-Val114) and GSTP1*D (Ile105-Val114). In SPP cases, there was no association between BCC numbers and GSTP1 BB, though the association with GSTP1 BC approached significance (P = 0.09). In MPP cases, GSTP1 BC was associated with BCC numbers (P = 0.03). We also found that the interaction term, GSTP1 Val105/Val105 with CCND1 AA, was associated with BCC numbers in the total (P = 0.001) and MPP (P = 0.006) but not SPP (P = 0.68) groups. In a stepwise model including GSTP1 Val105/Val105, CCND1 AA and their interaction terms as well as GSTM1, GSTT1 and CYP2D6 genotypes, skin type 1 and gender, the combination of genotypes was the best predictor of BCC numbers. These data su

Topics: Carcinoma, Basal Cell; Cyclin D1; Genotype; Glutathione Transferase; Humans; Middle Aged; Neoplasms, Multiple Primary; Occupations; Risk Factors; Skin Neoplasms