TY - JOUR TI - 17 beta-estradiol is a hormonal regulator of mirex tumor promotion sensitivity in mice AU - Porter, KL AU - Chanda, S AU - Wang, HQ AU - Gaido, KW AU - Smart, RC AU - Robinette, CL T2 - TOXICOLOGICAL SCIENCES AB - Mirex, an organochlorine pesticide, is a potent non-phorbol ester tumor promoter in mouse skin. Previous studies have shown that female mice are 3 times more sensitive to mirex tumor promotion than male mice and that ovariectomized (OVX) female mice are resistant to mirex promotion, suggesting a role for ovarian hormones in mirex promotion. To determine whether the ovarian hormone 17-β estradiol (E2) is responsible for the sensitivity of female mice to mirex promotion, female mice were initiated with DMBA; 2 weeks later groups of mice were OVX and implants, with or without E2, were surgically implanted subcutaneously. These mice were treated topically twice weekly with mirex for 26 weeks. E2 implanted OVX mice demonstrated high normal physiologic levels of serum E2 throughout the tumor promotion experiment. E2 implants restored by 80% the intact mirex-sensitive phenotype to the OVX mice. Consistent with a role for E2 and ERα and ERβ, treatment of DMBA-initiated female mice with topical ICI 182,780, an estrogen-receptor antagonist, reduced mirex tumor multiplicity by 30%. However, in cells co-transfected with ERα or ERβ and estrogen-responsive promoter reporter, mirex did not stimulate promoter reporter activity, suggesting that the promotion effect of mirex is downstream of ERα/β. Finally, a tumor promotion study was conducted to determine whether E2 implants could increase the sensitivity of male mice to mirex promotion. E2 implants in male mice did increase sensitivity to mirex promotion; however, the implants did not produce the full female sensitivity to mirex tumor promotion. Collectively, these studies indicate that E2 is a major ovarian hormone responsible for mirex tumor promotion sensitivity in female mice. DA - 2002/9// PY - 2002/9// DO - 10.1093/toxsci/69.1.42 VL - 69 IS - 1 SP - 42-48 SN - 1096-6080 KW - mirex KW - skin KW - 17 beta-estradiol KW - tumor promotion KW - endocrine ER - TY - JOUR TI - CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling AU - Zhu, SY AU - Yoon, K AU - Sterneck, E AU - Johnson, PF AU - Smart, RC T2 - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA AB - The basic leucine zipper transcription factor CCAAT/enhancer binding protein-beta (C/EBPbeta) is expressed in many cell types, including keratinocytes. C/EBPbeta activity can be increased by phosphorylation through pathways stimulated by oncogenic Ras, although the biological implications of Ras-C/EBPbeta signaling are not currently understood. We report here that C/EBPbeta-nullizygous mice are completely refractory to skin tumor development induced by a variety of carcinogens and carcinogenesis protocols, including 7,12-dimethylbenz[a]anthracene-initiation/12-O-tetradecanoylphorbol 13-acetate promotion, that produce tumors containing oncogenic Ras mutations. No significant differences in TPA-induced epidermal keratinocyte proliferation were observed in C/EBPbeta-null versus wild-type mice. However, apoptosis was significantly elevated (17-fold) in the epidermal keratinocytes of 7,12-dimethylbenz[a]anthracene-treated C/EBPbeta-null mice compared with wild-type mice. In v-Ha-ras transgenic mice, C/EBPbeta deficiency also led to greatly reduced skin tumor multiplicity and size, providing additional evidence for a tumorigenesis pathway linking Ras and C/EBPbeta. Oncogenic Ras potently stimulated C/EBPbeta to activate a C/EBP-responsive promoter-reporter in keratinocytes and mutating an ERK1/2 phosphorylation site (T188) in C/EBPbeta abolished this Ras effect. Finally, we observed that C/EBPbeta participates in oncogenic Ras-induced transformation of NIH 3T3 cells. These findings indicate that C/EBPbeta has a critical role in Ras-mediated tumorigenesis and cell survival and implicate C/EBPbeta as a target for tumor inhibition. DA - 2002/1/8/ PY - 2002/1/8/ DO - 10.1073/pnas.012437299 VL - 99 IS - 1 SP - 207-212 SN - 0027-8424 ER - TY - JOUR TI - Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis AU - Tiano, H. F. AU - Loftin, C. D. AU - Akunda, J. AU - Lee, C. A. AU - Spalding, J. AU - Sessoms, A. AU - Dunson, D. B. AU - Rogan, E. G. AU - Morham, S. G. AU - Smart, R. C. AU - al., T2 - Cancer Research DA - 2002/// PY - 2002/// VL - 62 IS - 12 SP - 3395–3401 ER -