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Environmental factors such as chemical toxicants contribute to the development of skin cancer by creating mutations in housekeeping genes and proto-oncogenes which disrupt intracellular signaling mechanisms. One vital signaling mechanism is tyrosine phosphorylation signaling. Phosphotyrosine signaling is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Recently we reported TC-PTP (PTPN2) is critical regulator of STAT3 signaling in mouse keratinocytes. To assess the role of TC-PTP in skin carcinogenesis, we generated epidermal-specific TC-PTP-deficient (K14Cre.PTPN2fl/fl) transgenic mice. Loss of TC-PTP led to a desensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes. TC-PTP deficiency in epidermis resulted in a significant increase in epidermal thickness and hyperproliferation (assessed by bromodeoxyuridine (BrdU) labeling index) compared to control mice following treatment with the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Consistently, primary keratinocytes derived from TC-PTP-deficient mice showed a faster growth rate. To further investigate the role of TC-PTP in skin carcinogenesis, TC-PTP-deficient mice were subjected to two-stage skin carcinogenesis analysis. TC-PTP-deficient mice showed a shortened latency of tumor development and significantly increased numbers of tumors compared to control mice, demonstrating TC-PTP deficiency predisposes mice to skin carcinogenesis. The data reveals TC-PTP may be a novel potential target for the prevention of skin cancer due to its role in the regulation of proliferation and apoptosis in epidermis. Citation Format: Hyunseung Lee, Mihwa Kim, Liza D. Morales, Thomas J. Slaga, John DiGiovanni, Dae J. Kim. Targeted disruption of T-cell protein tyrosine phosphatase in mouse epidermis reveals its critical role in chemically-induced skin carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4071.

In this study, we conducted a comprehensive examination of a series of pentacyclic tritperpenes found in P. frutescens, including ursolic acid (UA) oleanolic acid (OA), augustic acid (AA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) for their effects on epidermal cell signaling, proliferation, and skin inflammation in relation to their ability to inhibit skin tumor promotion by TPA. For these experiments, female ICR mice (7-9 weeks of age) were treated with either acetone or 2 μmol of UA, OA, AA, CA, 3-epiCA, MA, or 3-epiMA 30 min prior to TPA (6.8 nmol) treatment The treatment protocol involved twice weekly treatments over a two week period. Mouse epidermis (6 hr time point) and whole skin (48 hr time point) were collected for Western blot analysis and histological analysis, respectively. Pretreatment with these compounds inhibited the activation of JNK1/2, Src, and Stat3 as well as the induction of Cox-2 protein. Pretreatment with the compounds also reversed the effect of TPA on PDCD4 and p27, and increased the activation of AMPK and LKB1. We also examined the effect of the compounds on TPA-induced epidermal hyperproliferation as assessed by epidermal thickness and epidermal labeling index (LI). All of the compounds examined significantly inhibited TPA-induced epidermal hyperproliferation (significant reductions in both epidermal thickness and LI). In addition, the effect of the triterpenes on TPA-induced infiltration of mast cells in dermis was evaluated. UA significantly inhibited the infiltration of dermal mast cells induced by TPA. Notably, OA, AA, CA, 3-epiCA, MA, and 3-epiMA produced a greater inhibitory effect than that seen with UA on the number of infiltrated mast cells. Thus, UA and a series of related triterpenes differentially inhibited multiple signaling pathways, epidermal hyperproliferation, and a marker of skin inflammation (infiltrated mast cells) induced by TPA. Several of the compounds including CA, 3-epiCA, MA, and 3-epiMA were particularly effective in these experiments. We are currently testing the ability of this group of compounds to inhibit skin tumor promotion by TPA in a two-stage skin carcinogenesis experiment. Collectively, the current data suggest that several pentacyclic triterpenes, in addition to UA, may have potent chemopreventive activity. Research supported by CA164159. Citation Format: Jiyoon Cho, Okkyung Rho, Jacob Junco, Thomas J. Slaga, Andrew M. Camelio, Dionicio Siegel, John DiGiovanni. Anti-skin tumor promoting effects of pentacyclic triterpenes found in Perilla frutescens. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1899. doi:10.1158/1538-7445.AM2015-1899

Chronic exposure of UV radiation can contribute to the development of skin cancer by promoting PTK signaling. Studies show that exposure to UV radiation increases the ligand-independent activation of PTKs and induces PTP inactivation. In the present work, we report that TC-PTP activity is stimulated during the initial response to UVB irradiation which leads to suppression of keratinocyte cell survival and proliferation via the down-regulation of STAT3 signaling. Our results show that TC-PTP-deficient keratinocyte cell lines expressed a significantly increased level of phosphorylated STAT3 after exposure to low dose UVB. This increase corresponded with increased cell proliferation in TC-PTP-deficient keratinocytes following UVB irradiation. Loss of TC-PTP also reduced UVB-induced apoptosis. In corroboration with these results, overexpression of TC-PTP in keratinocyte cell lines yielded a decrease in phosphorylated STAT3 levels, which corresponded with a significant decrease in cell proliferation in response to low dose UVB. We demonstrate that TC-PTP activity was increased upon UVB exposure and overexpression of TC-PTP in keratinocyte cell lines further increased its activity in the presence of UVB. Treatment of TC-PTP-deficient keratinocytes with the STAT3 inhibitor STA21 significantly reduced cell viability following UVB exposure in comparison with untreated TC-PTP-deficient keratinocytes, confirming that the effect of TC-PTP on cell viability is mediated by STAT3 dephosphorylation. Combined, our results indicate that UVB-mediated activation of TC-PTP plays an important role in the STAT3-dependent regulation of keratinocyte cell proliferation and survival. Furthermore, these results suggest that TC-PTP may be a novel potential target for the prevention of UVB-induced skin cancer. Note: This abstract was not presented at the meeting. Citation Format: Hyunseung Lee, Mihwa Kim, Liza D. Morales, Thomas J. Slaga, Dae Joon Kim. Activation of T-cell protein tyrosine phosphatase suppresses keratinocyte survival and proliferation following UVB irradiation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4567. doi:10.1158/1538-7445.AM2015-4567

Ultraviolet (UV) radiation is the primary cause of human skin cancer. Signal transducer and activator of transcription 3 (Stat3) is one of the key regulators of epidermal cell survival and proliferation during the development of UV-induced skin cancer. We have previously shown that T-cell protein tyrosine phosphatase (TC-PTP) contributes to the rapid dephosphorylation /deactivation of Stat3 in response to UVB irradiation in keratinocytes. In the current work, we investigated the functional role of TC-PTP in keratinocyte survival and proliferation following UVB exposure. Knockdown of TC-PTP in mouse keratinocytes using siRNA significantly reduced apoptosis following UVB irradiation in comparison with control keratinocytes as evidenced by the decreased levels of activated caspase-3 and PARP cleavage. This reduction corresponded with an increased level of phososphorylated Stat3 in TC-PTP-deficient keratinocytes. Knockdown of TC-PTP in keratinocytes also significantly increased cell proliferation following UVB irradiation compared with control keratinocytes. Similar with these results, overexpression of TC-PTP in keratinocytes significantly increased apoptosis and decreased cell proliferation in response to UVB irradiation compared with control keratinocytes, which corresponded with a decreased level of phosphorylated Stat3. Further studies using TC-PTP-deficient keratinocyte cell lines showed that cell viability was increased in TC-PTP-deficient cells following UVB irradiation. Treatment of TC-PTP-deficient keratinocytes with specific Stat3 inhibitor, STA21 significantly reduced cell viability, upon UVB exposure in comparison with untreated TC-PTP-deficient keratinocytes, which suggests that the effect of TC-PTP on cell viability is mediated by Stat3 dephosphorylation. Combined, our results indicated that TC-PTP plays an important role in the regulation of keratinocyte proliferation and survival after UVB exposure via modulation of Stat3 signaling. Furthermore, these results suggest that TC-PTP may be a novel potential target for the prevention of UVB-induced skin cancer. Citation Format: Young S. Lee, Jun W. Shin, Liza D. Morales, Thomas J. Slaga, Dae J. Kim. The role of T-cell protein tyrosine phosphatase (TC-PTP) in UVB-induced epidermal cell proliferation and survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3591. doi:10.1158/1538-7445.AM2013-3591

In recent years, emerging evidence suggests that cancer chemopreventive agents when combined might be more effective than when given alone. Both UA and Res have been shown to reduce inflammation and tumor development in various tissues. In mouse skin, both compounds have been shown to block skin tumor promotion by TPA and reduce TPA-induced inflammation. In this study, we have further evaluated the effect of UA and Res on skin tumor promotion with emphasis on examining combinations of these agents. For these experiments, UA, Res and combinations of UA + Res were applied topically (various doses) prior to TPA treatment on mouse skin. The combination of UA + Res showed additive and possibly synergistic inhibition of TPA-induced epidermal hyperproliferation as assessed by both epidermal hyperplasia and BrdU labeling index. The effect of UA, Res and the combination of UA + Res on epidermal signaling pathways was also evaluated. The combination of UA + Res significantly inhibited activation of epidermal Akt, NF-κB, p38 MAPK, and JNK in response to TPA treatment compared to the treatment with the individual compounds. The combination of UA + Res also dramatically reduced the induction of epidermal Cox-2 by TPA. Notably, combined treatment with UA and Res induced a dramatic increased phosphorylation of AMPK-α suggesting that AMPK activation may also play a critical role in the ability of the combination to alter skin tumor promotion. Combination treatment during skin tumor promotion showed greater inhibition of tumor multiplicity than with either agent alone. In further experiments, the effect of UA, Res and UA + Res on proliferation of bulge-region keratinocyte stem cells (KSCs) was evaluated. Both UA and Res treatment inhibited TPA-induced proliferation and migration of bulge-region KSCs. Furthermore, the combination of UA + Res appeared to be more effective at blocking proliferation of these cells from the hair follicle when compared with the single compound-treated groups. Taken together, these data suggest that the combination of UA + Res has either additive or synergistic inhibitory effects on keratinocyte proliferation (including KSCs) and various signaling pathways. These effects may explain the greater inhibition of skin tumor promotion by the combination of UA and Res. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1596. doi:1538-7445.AM2012-1596

Ultraviolet B radiation (UVB) can cause DNA damage, induce gene mutations and modulate intracellular signal transduction contributing to the development of skin cancer. Signal transducer and activator of transcription 3 (Stat3) modulates various physiological functions, including apoptosis, cell cycle regulation, and tumor angiogenesis through regulation of gene expression, and its constitutive activation is associated with human epithelial cancers. Recent studies demonstrated that T-cell protein tyrosine phosphatase (TC-PTP) dephosphorylates activated Stat3 in keratinocytes after UVB irradiation. In the current work, we report that TC-PTP translocates from the cytosol to the nucleus and dephosphorylates Stat3 following UVB irradiation in keratinocytes. Western blot analysis showed that TC-PTP mainly localized in the cytoplasm of keratinocytes and translocated from cytoplasm to nucleus upon UVB irradiation. Immunofluorescence analysis of the exogenous expression of TC-PTP confirmed its nuclear translocation, and showed that nuclear translocation of TC-PTP occurs independently of its phosphatase activity. Nuclear translocation of TC-PTP was increased with increased dose of UVB exposure. Dephosphorylation of Stat3 by TC-PTP was enhanced after UVB irradiation of cultured keratinocytes with nuclear accumulation of TC-PTP. Knockdown of TC-PTP with siRNA suppressed dephoshorylation of Stat3 and enhanced cell viability in response to UVB irradiation. UVB irradiation also induced expression of 14-3-3α, a protein that has been shown to be involved in the transport of proteins. Further studies revealed that UVB-induced nuclear translocation of TC-PTP was effectively inhibited by knockdown of 14-3-3α, suggesting 14-3-3α is involved in nuclear import of TC-PTP. These results indicate that TC-PTP plays an important role as a regulator of Stat3 signaling in keratinocytes upon UVB irradiation. Nuclear translocation of TC-PTP is regulated by a 14-3-3α-dependent signaling pathway, resulting in the rapid dephosphorylation of activated Stat3 in the nucleus. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2537. doi:1538-7445.AM2012-2537

Resveratrol (RES), found in grapes and Ursolic Acid (UA), found in rosemary and apples, delay the onset and reduce the number of experimentally-induced skin tumors in mice and inhibit the oncogenic Akt/mammalian target of rapamycin (Akt/mTOR) and Nuclear Factor kappa B (NF\#954;B) pathways. Based on their similar downstream effects via different proximal targets, we hypothesized that a combination treatment of RES and UA would synergize to produce a stronger inhibitory effect on skin tumor promotion. Methods: The dorsal skin of FVB mice (n=8) were shaved and treated topically twice per week for 2 weeks with sub-optimal doses of 2 μmol UA, 2 μmol RES, or a combination of both in 200 μL acetone. Each treatment was followed 30 minutes later with topical application of 3.4 nmol of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in 200 μL acetone. Animals were sacrificed either 6 h (Western blotting) or 48 h (histology) after the final TPA treatment. The skins of five mice per group were removed and the epidermis was collected by scraping for Western blotting. For immunohistochemical (IHC) analysis of epidermal proliferation three mice per group were i.p. injected with 100 mg/kg Bromodeoxyuridine (BrdU) in PBS 30 min. prior to sacrifice. Mouse skin from treated areas was fixed in formalin, paraffin embedded, and analyzed via IHC. Results: RES and UA in combination had a stronger effect on hallmarks of skin tumor promotion than was expected based on the sum of their individual inhibitory effects, indicating synergism between RES and UA. RES and UA in combination synergistically inhibited TPA-induced epidermal thickening (80.2% inhibition vs 66.1 % expected) and epidermal proliferation (100.0% inhibition vs 90.0% expected). Western blotting revealed that components of the NF\#954;B and Akt/mTOR pathways were synergistically downregulated by the RES + UA combination in mouse epidermis. TPA-induced Akt (thr308) phosphorylation (86.0% inhibition vs 26.6% expected) and NFkB subunit p65 (ser536) phosphorylation (100.0% inhibition vs 73.3% expected) were suppressed to a much stronger degree with the combination treatment than that predicted. Similar results were seen for other pathway components, such as p70S6K and ribosomal S6. The synergistic activities of RES and UA were also manifest in the HaCaT human keratinocyte cell line. Cells were treated with sub-optimal doses of RES, UA, or RES + UA and stimulated with 10 ng/ml human tumor necrosis factor alpha (TNFα) for 30 min. and cell lysates were analyzed via Western blotting. TNFα-mediated phosphorylation of p65 was not inhibited by 25 μM RES or 0.1 μM −1 μM UA, but combinations of RES + UA resulted in strong synergistic inhibition of p65 phosphorylation (>66% inhibition vs 0% expected). Also, when HaCaT cells were treated with NFkB- and Akt/mTOR-inhibitory doses of RES (150 μM-200 μM) and UA (5 μM-10 μM), a strong increase (5 fold) in phosphorylation/activation of the energy sensing AMP-activated protein kinase (AMPK) was observed by Western blotting. AMPK also inhibits NF\#954;B and Akt/mTOR activities in other systems, suggesting that AMPK activation may function as a mediator of the synergistic anti-tumor promoting effects of RES and UA. Conclusions: These results indicate that UA and RES synergize to inhibit markers of tumor promotion in both in vivo and in vitro skin models. Future studies will further elucidate the synergistic mechanism of RES and UA and also determine if RES and UA have a synergistic preventive effect on skin tumor promotion during two-stage skin carcinogenesis in vivo. Supported by NIH grants CA079065, supplemental CA079065-10S1 (ARRA), CA129409 and CA037111. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B59.

The purpose of our study was to determine the effect of combined action of phytochemicals on early stages of skin tumorgenesis, i.e., initiation and promotion. We tested calcium D-glucarate (CG) given in the diet, while resveratrol (RES) and ursolic acid (URA) were applied topically. The 7,12-dimethylbenz[a]anthracene (DMBA)-initiated, 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted multistage skin carcinogenesis model in SENCAR mice was used. Mice (6-7 weeks old) with shaved backs received one topical dose of DMBA (20 nmol), then after one month, two weekly doses (2 µg each) of TPA (tumor promoter) for 14 weeks until sacrifice. The phytochemicals RES (2.5 μmol) or URA (1 μmol) were applied topically 20 min prior to DMBA or TPA treatment and 2% dietary CG was given in the AIN-93G diet from 2 weeks prior to 2 weeks after the DMBA dose or continually beginning 2 weeks prior to the first dose of TPA. We determined the tumor incidence (% of mice with tumors) and tumor multiplicity (number of tumors per mouse) and using RT-PCR and immunochistochemical analyses, we checked the expression of some cell proliferation and inflammation related genes. URA applied alone and in combination with CG during the promotion stage was a strong inhibitor of tumor multiplicity and tumor incidence. Combinations of URA with dietary CG appeared to show some synergistic effects. All compounds and their combinations reduced epidermal proliferation, but only URA and a combination CG/URA applied during promotion significantly reduced hyperplasia, as determined by epidermal thickness measurements taken at 14 weeks of TPA treatment. DMBA/TPA treatments resulted in epidermal hyperplasia, characterized by significant increase in transcription factor AP-1 components and nuclear factor kappa B (NFkB) expression levels with a simultaneously increased expression of the inflammation markers COX-2 and IL-6, compared to untreated controls. All anti-promotion treatments (either single compounds or their combinations) caused a marked decrease of inflammation related genes levels compared to the DMBA/TPA control. On the other hand, only URA and URA with dietary CG diminished the induced expression of proto-oncogenes c-jun and c-fos (components of AP-1) and the expression of NFkB protein p50. These results show that URA is a potent inhibitor of skin tumor promotion and it may be useful in the prevention of skin cancer and other epithelial cancers in humans. Supported by NIH grants CA 102747 and P30 CA 54174-16S1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3470.

The aim of this study was to determine the anti-cancer potential of the phytonutrient ursolic acid (UA) in a UV-treated HaCaT human keratinocyte cell line. Earlier studies have shown UA strongly inhibits DMBA/TPA-mediated carcinogenesis in SENCAR mice, but effects of UA on UV-induced skin cancer are unknown. Our hypothesis was that treating cells with UA, found in plant sources including rosemary and apple, may inhibit UV-induced cell death, ROS production, and transcription and activation of oncogenes and oncoproteins. These in vitro studies would suggest UA may inhibit UV-mediated skin carcinogenesis. HaCaT cells were seeded at 2,000 cells/well for MTT and DHR assays, and at 1.6 × 104 cells/cm2 for RT-PCR and Western blotting. 24 hours after seeding, cells were treated with concentrations of UA up to 25 μM. Cells were UV-treated with various doses using a transilluminator emitting 36% of its energy in the UVA range and 64% in the UVB range with a peak of 312 nm. For cell death assays, cells were incubated for 4 hours in media with MTT, UV treated, then dissolved in DMSO after various timepoints prior to measuring the absorbance at 570 nm. For quantification of intracellular H2O2, cells were incubated in media containing 5 µM DHR 123 for 1 hour prior to UV-treatment, followed by reading fluorescence at 530 nm with an excitation of 485 nm. RT-PCR was performed for bcl-2 and c-jun using SYBR green probe. Western blotting for phospho-p38 MAPK was done with whole cell lysates, isolated using RIPA buffer. Phospho-p65 and phospho-c-jun were quantified by blotting nuclear and cytosolic fractions, which were isolated using a hypotonic/hypertonic nuclear extraction procedure. We find that treating cells for 24 hours before UV and 12 hours post-UV with non-toxic doses of UA does not protect cells from UV-death. Also, pretreating this cell line with these doses of UA does not inhibit a UV-induced rise in intracellular H2O2 within an hour post-UV. However, RT-PCR results show UA treatment exacerbates a UV-induced rise in bcl-2 RNA levels and inhibits a UV-mediated increase in c-jun RNA 1 hour post-UV. Also, Western blotting reveals that 25 μM UA inhibits a 500 mJ/cm2-induced increase in phospho-p38 MAPK by 85%, and that treatment with 10 μM UA reduces 100 mJ/cm2-initiated nuclear accumulation of oncogenic phospho-c-jun by 47.6%, 1 hour after UV. Finally, treatment with 10 and 25 μM UA dose-dependently contributes to a decrease in nuclear phospho-p65 seen 1 hour post-UV treatment. These in vitro results show UA may prevent UV-mediated skin cancer by modulating the activities of the oncogenic transcription factors AP-1 and NFκB. Supported by NIH grants CA 102747 and P30 CA 54174-16S1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5657.

Glucocorticoids are very effective in preventing carcinogen- and tumor promoter-induced skin inflammation, hyperplasia, and mouse skin tumor formation when applied to skin together with a carcinogen. Their control of cellular functions is mediated by a well-known transcription factor, glucocorticoid receptor (GR). GR acts via two different mechanisms: transcriptional regulation that requires DNA-binding and protein-protein interaction between GR and other transcription factors, such as nuclear factor kappa B (NF-κB) or activator protein 1 (AP-1), which is independent of DNA binding. We hypothesize that only the transrepression activities of the GR are sufficient to suppress skin tumor development. To test our hypothesis, we have synthesized two glucocorticoids (RU24858 and RU24782) that induce only transrepression activities of the GR. These two compounds are able to bind to the GR with high affinity and repress the AP-1 and NF-κB activity while showing reduced transactivation activities in vitro. Different doses (0.001, 0.01 and 0.1 mg) of RU24858, RU24782, desoxymethasone (DES) and fluocinolone acetonide (FA) or acetone were applied to the dorsal skin of female SENCAR mice 20 min. prior to TPA application (2 μg), two times per week for two weeks. Keratinocytes proliferation rates were estimated by measuring epidermis thickness and BrdU incorporation index. Immunohistochemistry and RT-PCR techniques were also used to evaluate expression level of genes involved in inflammation and cell cycle regulation. All studied compounds did not influence keratinocytes proliferation when applied alone. Application of DES, FA and RU24858 reversed TPA induced hyperplasia, in dose-depended manner, while RU24782 treatment had no effect on epidermis thickness or the BrdU incorporation index in TPA treated skins. All tested compounds were able to decrease c-jun mRNA level both in acetone and TPA-treated skins. DES, FA and RU24858 were also able to decrease elevated by TPA mRNA level of IL-6, COX-2 and iNOS. RU24782 did not influence mRNAs levels of these genes. These findings suggest that RU24782 had no effect on TPA-induced inflammation and hyperplasia in SENCAR mice, while RU24858 was able to reduce all tested inflammation markers, having only slight effect on epidermal hyperplasia. Supported by NIH grants CA 0796065-06 and P30 CA 54174-16S1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2477.