|
 |
|
EDRI Federal Project Inventory:
64081-01a1 Alkyl PCDFs–Inhibition of Mammary Cancer
- Sponsor Organization: NIH/NCI
- Project Title: 64081-01A1 ALKYL PCDFS--INHIBITION OF MAMMARY CANCER
- Project Focus: HUMAN HEALTH EFFECTS
- Description: Previous studies have demonstrated that 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD) inhibits a broad spectrum ofestrogen-induced responses
in the female rat uterus and in MCF-7 human breast cancer cells. TCDD
also inhibitsmammary tumor formation in rats and in mice transplanted
with MCF-7 cells. 6-Methyl-1,3,8-trichlorodibenzofuran(MCDF) and
related alkyl polychlorodibenzofurans (PCDFs) are relatively non-toxic
analogs of TCDD which exhibitcomparable in vitro and in vivo
antiestrogenic and antitumorigenic activities. Thus, the alkyl
PCDFs represent a newclass of antiestrogens which act through the aryl
hydrocarbon (Ah) receptor signal transduction pathway and thus mayhave
clinical potential as chemotherapeutic agents for treatment of breast
cancer. TCDD and MCDF, are potentantiestrogens in T47D and MCF-7 human
breast cancer cells (ER- and AhR-positive, ER+AhR+) but exhibit
minimalactivity in ER-AhR-MDA-MB-231 cells. The in vitro or in vivo
effects of alkyl PCDFs or TCDD on ER-AhR+ orER+AhR- cells have not
been previously investigated due to the unavailability of these cell
lines. Experiment 1 of thisproject will thoroughly characterize a
series of ER-AhR+ and ER+AhR- variant breast cancer cell lines.
ER+AhR- cellswill be isolated by culturing MCF-7 and T47D cells in 1
micromole benzo[a]pyrene (BaP) and the ER+AhR- variant cell lines will
be fully characterized. ER-AhR+ variant cells will be isolated from
high passage T47D cells and fromMDA-MB-231 cells (ER-AhR-) stably
transfected with the human arnt gene which restores Ah- responsiveness
in thiscell line. The resultant stable transfectants will represent an
ER-AhR+ phenotype which hitherto has not been described. Moreover,
since MDA-MB-231 cells are resistant to endocrine and cytotoxic drug
therapy, the ER-AhR+ cells willserve as a model for assessing the
antitumorigenic and antiproliferative effects of AhR agonists (e.g.
alkyl PCDFs) inthese cells. Although the growth of MDA-MB-231 cells
are estrogen-independent, various growth factors (IGF-l, EGF,TGFalpha,
insulin) act as mitogens and, therefore, growth factor-induced
proliferation and a number of othercharacteristics of the ER-AhR+
stable transfectant cell lines will be thoroughly.investigated. Immune
deficient micetransplanted with breast cancer cells will be utilized
in Experiment 2 to (a) determine the factors which control
thedevelopment of tumors in athymic mice transplanted with the wild-
type and variant breast cancer cell lines characterizedin Experiment 1
and (b) assess the relative potencies of TCDD and the alkyl PCDFs as
chemotherapeutic agents in thisin vivo model. In parallel studies, the
relative potencies of the alkyl PCDF as antiestrogens will also be
determined in thefemale rat uterus. These short-term studies will
provide critical relative potency data for this series of alkyl PCDFs
in awell-established estrogen-responsive target organ and prioritize
their use in in vivo studies (Experiment 4) on theantitumorigenicity
of selected congeners in the DMBA-induced rat tumor model. These
proposed studies will providecritical new data on the mechanism of
action of AhR agonists as antiestrogens and antitumorigenic agents in
two in vivomodels and determine which alkyl PCDFs should be further
investigated as potential chemotherapeutic agents fortreatment of
mammary cancer.
- References:
- Category: MODELS
- Subcategory: BASIC RESEARCH
- Keywords for Experimental System/Species: LABORATORY STUDY
- Keywords for Experimental Endpoints: CARCINOGENESIS, AH RECEPTOR
- Chemical Agents: TCDD, ARYL HYDROCARBONS, POLYCHLORINATED DIBENZOFURANS, METHYL-1,3,8-
TRICHLORODIBENZOFURAN
- Performing Institution: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- Contact: CONTRACT PERSON: ELAINE C. LEE; BUILDING 31; 11A21; NATIONAL CANCER
INSTITUTE, NIH,BETHESDA, MD 20892-2590; 301-496-5515;
LEEE@OD.NCI.NIH.GOV
|
|
