CORRELATION OF IN-VITRO AND IN-VIVO GROWTH SUPPRESSION OF MCF-7 HUMANBREAST-CANCER BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN

The purpose of this study was to compare the effect of 2,3,7,8-tetra-c hlorodibenzo-p-dioxin (TCDD) on the in vitro and in vivo 17beta-estrad iol (E2)-dependent growth of MCF-7 human breast cancer cells. In cultu re. a major component of postconfluent growth of MCF-7 cells is E2 dep endent. In vivo, MCF-7 cells fail to grow as xenografts without exogen ous E2 support. Thus the effect of TCDD on postconfluent MCF-7 growth in culture was compared with its effect on MCF-7 xenograft growth in i mmunosuppressed mice. A concentration of 10(-9) M E2 was optimal for s upporting postconfluent growth of MCF-7 cells in culture into multicel lular aggregates (foci) on a monolayer background. The 50% inhibitory dose of TCDD under these conditions was 3 x 10(-10) M, while E2-depend ent focus development was completely inhibited by 10(-8) M TCDD. Weekl y i.p. administration or TCDD (5 mug/kg) to mice bearing MCF-7 tumor x enografts resulted in inhibition of the tumor growth rate for the firs t 2 weeks, followed by recovery to the control growth rate during the third week. These recovered tumors were round to retain estrogen-depen dent growth as shown by second generation transplantation studies. The p.o. route of TCDD administration yielded a similar 2-week transient suppression of growth with a concentration of 8 mug/kg TCDD/kg body we ight but only a 1-week growth rate latency with a 2-mug/kg body weight dose. A single 5-mug/kg dose given 1 day after implantation was virtu ally noninhibitory. These results indicate that TCDD suppression of es trogen-dependent MCF-7 human breast cancer cell growth in vitro was pr edicative of a similar growth suppression of MCF-7 solid tumor xenogra fts in However, additional host-related factors must be involved in vi vo, since suppression or tumor growth is transient. These studies prov ide a basis for future in vivo investigations of TCDD endocrine toxici ty by using the MCF-7 tumor as a surrogate estrogen-responsive human o rgan and to examine the efficacy of TCDD and related Ah receptor-media ted compounds in the management of human estrogen-dependent breast can cer.