Abstract 3707: Early stage inhibition of murine mammary carcinogenesis by ultraviolet radiation.

Abstract

Abstract Epidemiological studies of geographical variations in breast cancer mortality rates have found increased death rates at higher latitudes in USA and other countries 1. This breast cancer latitudinal gradient is hypothesized to be mediated by ultraviolet radiation (UVR) - produced vitamin D3. We first have tested this latitudinal hypotheses using the well-described C3(1)/Tag transgenic murine mammary carcinogenesis model2. We have found that UVR significantly prolongs palpable tumor - free survival (135±23 vs.118±18 days) and reduces the tumor burden and multiplicity (2.9±1.6 vs. 7.2±2.3 tumors), but does not alter the time between the appearance of the first palpable tumor and death in Tag female mice. Therefore we have focused on the effects of UVR on earlier stage carcinogenesis. Tag transgenic female mice have a time-dependent increase in the incidence of ductal carcinoma in situ (DCIS) - like incidence. Thus, Tag mice develop ductal epithelial atypia in 50% of mice at age 8 wks, with progression to intraepithelial neoplasia (resembling human DCIS) in 70-90% of mice (in at least one gland) at 10-13 wks, and DCIS-like changes and early invasion in 100% of mice at age 14-15 wks. We compared weekly the similarity of histological changes between the pairs of mammary glands and found no significant gland site-to-gland site variations. UVR treatment, 350mJ/cm2 thrice weekly from age 6 wks to 15 wks, reduced both the percentage of DCIS-bearing mice (65, 60, 51, 32 and 20% reduction at week 8, 9, 11, 13 and 14) and the percentage of DCIS-bearing glands in each animal (82, 55, 66, 20 and 19% reduction at week 9, 11, 13, 14 and 15). The mechanism of the UVR-mediated prevention of the murine mammary carcinogenesis is unclear but there is evidence favoring a Hedgehog (HH) signaling-dependent mechanism, since D3 is a potent inhibitor of the HH signaling pathway, which is upregulated in many cancers including breast cancer3-5. Consistent with this idea we found that UVR reduces DCIS-like changes in Ptch+/- mice. Taken together our results support our hypothesis that inhibition of early stage mammary carcinogenesis by UVR-produced vitamin D3 underlies the latitudinal gradient. 1. Garland, F. C. et all. Prev Med 1990, 19, 614-22. 2. Green, J. E. et all. Oncogene 2000, 19, 1020-7. 3. Bijlsma, M. F. et all. PLoS Biol 2006, 4, e232. 4. Moraes, R. C. et all. Development 2009, 136, 1423-32. 5. Lewis, M. T. et all. Development 1999, 126, 5181-93. Citation Format: Anastasia M. Makarova, Grace Wang, Lynn Wang, Joy Wang, Yefim Khaimskiy, Ervin H. Epstein. Early stage inhibition of murine mammary carcinogenesis by ultraviolet radiation. [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 3707. doi:10.1158/1538-7445.AM2013-3707