Aryl hydrocarbon receptor activation during pregnancy, and in adult nulliparous mice, delays the subsequent development of DMBA-induced mammary tumors.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the prototypic ligand for the aryl hydrocarbon receptor (AhR), promotes tumor formation in some model systems. However, with regard to breast cancer, epidemiological and animal studies are inconclusive as to whether exposure increases tumor incidence or may instead be protective. We have previously reported that mice exposed to TCDD during pregnancy have impaired differentiation of mammary tissue, including decreased branching and poor development of lobuloalveolar structures. Because normal pregnancy-induced mammary differentiation may protect against subsequent neoplastic transformation, we hypothesized that TCDD-treated mice would be more susceptible to chemical carcinogenesis after parturition. To test this, mice were treated with TCDD or vehicle during pregnancy. Four weeks later, 7,12-dimethylbenz[a]anthracene (DMBA) was administered to induce mammary tumor formation. Contrary to our hypothesis, TCDD-exposed parous mice showed a 4-week delay in tumor formation relative to controls, and they had a lower tumor incidence throughout the 27-week time course. The same results were obtained in nulliparous mice given TCDD and DMBA on the same schedule. We next addressed whether the delayed tumor incidence was a reflection of decreased tumor initiation, by testing the formation of DMBA-DNA adducts and preneoplastic lesions, induction of cytochrome P450s, and cell proliferation. None of these markers of tumor initiation differed between vehicle- and TCDD-treated animals. The expression of CXCL12 and CXCR4 was also measured to address their possible role in tumorigenesis. Taken together, our results suggest that AhR activation by TCDD slows the promotion of preneoplastic lesions to overt mammary tumors.
Department of Pharmaceutical Sciences, Washington State University, Pullman, WA, USA.
Tao
T
Wang
Heather M
HM
Gavin
Volker M
VM
Arlt
B Paige
BP
Lawrence
Suzanne E
SE
Fenton
Daniel
D
Medina
Beth A
BA
Vorderstrasse
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D005260:Female; D008024:Ligands; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins; D011230:Precancerous Conditions; D011247:Pregnancy; D011270:Pregnancy, Animal; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
D002273:Carcinogens; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D015127:9,10-Dimethyl-1,2-benzanthracene