Diindolylmethane Inhibits Cervical Dysplasia, Alters Estrogen Metabolism, and Enhances Immune Response in the K14-HPV16 Transgenic Mouse Model

Abstract

This study was designed to establish whether 3,3′-diindolylmethane (DIM) can inhibit cervical lesions, alter estrogen metabolism in favor of C-2 hydroxylation, and enhance immune function in the K14-HPV16 transgenic mouse model. Mice were bred, genotyped, implanted with E 2 pellets (0.25 mg/90-day release) under anesthesia, and divided into groups. Wild-type and transgenic mice were given either AIN76A diet alone or with 2,000 ppm DIM for 12 weeks. Blood and reproductive tracts were obtained. Blood was analyzed for estrogen metabolites and IFN-γ. The cervical transformation zone was sectioned and stained for histology. Estradiol C-2 hydroxylation and serum IFN-γ levels were significantly increased over controls in wild-type and transgenic mice receiving DIM. In wild-type mice without DIM, hyperplasia of the squamous epithelium was observed. Wild-type mice fed DIM displayed a normal thin epithelium. In transgenic mice without DIM, epithelial cell projections into the stroma (papillae) were present. An additional degree of nuclear anaplasia in the stratum espinosum was observed. Dysplastic cells were present. Transgenic mice fed DIM displayed some mild hyperplasia of the squamous epithelium. DIM increases estrogen C-2 hydroxylation in this model. Serum INF-γ was increased, indicating increased immune response in the DIMfed animals. Histopathology showed a marked decrease in cervical dsyplasia in both wild-type and transgenic mice, indicating that DIM delays or inhibits the progression from cervical dysplasia to cervical cancer. Using the K14-HPV16 transgenic mouse model, we have shown that DIM inhibits the development of E6/ E7 oncogene-induced cervical lesions. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2957-64)

TALEN-mediated targeting of HPV oncogenes ameliorates HPV-related cervical malignancy

“…The HPV16 probe was constructed by nick translation of the HPV16 plasmid with digoxigenin and detected the National Cancer Institute (NCI) Mouse Repository (Frederick, Maryland, USA) [strain nomenclature: FVB.Cg-Tg(KRT14-HPV16) wt1Dh] and bred at the Experimental Animal Center, HUST. Breeding and genotyping of the offspring is described elsewhere in detail (39). HPV16-positive female mice (6 to 8 weeks old) were randomly grouped.…”

Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

“…70 Murine models have also shown evidence of a favorable effect of DIM on estrogen metabolism in relation to breast cancer risk. Sepkovic et al 71 exposed wild-type mice to standard chow or standard chow plus 0.2% (2000 ppm) DIM for 12 weeks and found enhanced interferon-c response and lower estradiol concentrations in those fed DIM compared with those fed control chow. It should be noted that the DIM supplementation approximated a 1000-mg single dose in humans.…”

Identification of Androgen Receptor and Beta-Catenin Target Genes in Prostate and Prostate Cancer

“…In breast and neuronal cells, estrogen increases β-catenin expression, and activated estrogen receptor α (ERα) and β-catenin directly interact (20)(21)(22)(23). Also, a drug that can reduce estrogen signaling, Indole-3-carbinol (I3C), prevents cervical cancer in HPV16-infected mice and was highly effective in inducing precancerous lesion regression in women (24)(25)(26). These effects may be due to the fact that I3C can also degrade β-catenin in prostate cancer cells (27).…”