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1.
Cancer Res ; 65(3): 879-86, 2005 Feb 01.
Article in English | MEDLINE | ID: mdl-15705886

ABSTRACT

Wild-type erbB-2/neu transgenic mice were used to study the interactions between tamoxifen and dietary phytoestrogens (or isoflavones) by dose and form in vivo. Mice were randomized to one of four dietary formulas and implanted with an 8-week continuous-release tamoxifen or placebo pellet at 8 weeks of age. In placebo-treated mice, soy meal diet (but not diets supplemented with low-dose or high-dose isoflavones or a casein diet) resulted in prolongation of tumor latency. In tamoxifen-treated mice fed the soy meal, casein, or high-dose isoflavone enriched diets, the majority (>80%) showed no tumor formation by 60 weeks of age. Of the mice that developed tumors, latency was significantly prolonged. In tamoxifen-treated mice fed the low-dose isoflavone enriched diet, a much higher rate of mammary tumor development (>50%; P < 0.002) and a shorter tumor latency were observed. In vitro studies of human and mouse mammary tumor cell lines confirm that low doses of genistein, co-administered with tamoxifen, promote cell proliferation. This is in contrast to tamoxifen alone or tamoxifen with higher doses of genistein that are growth inhibitory. In summary, low-dose dietary isoflavones abrogated tamoxifen-associated mammary tumor prevention in vivo. These interactions are supported by in vitro data from human and mouse mammary tumor cell lines. These dose-associated interactions likely have relevance to the human use of tamoxifen for prevention or treatment of breast cancer.


Subject(s)
Breast Neoplasms/prevention & control , Mammary Neoplasms, Experimental/prevention & control , Phytoestrogens/pharmacology , Tamoxifen/pharmacology , Animals , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Interactions , Female , Humans , Isoflavones/adverse effects , Isoflavones/pharmacology , Mice , Mice, Transgenic , Phytoestrogens/adverse effects , Tamoxifen/antagonists & inhibitors
2.
Comp Med ; 54(3): 280-7, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15253274

ABSTRACT

Phenotypic and biological heterogeneity was studied in a single transgenic mouse model to determine the level of biological variance. We analyzed 1,258 tumors from 417 MMTV-wt-ErbB-2 transgenic mice, subdivided by casein or soy-based dietary randomization and hormonal treatment. Variance in tumor histologic features, growth pattern, invasion, metastases, and multi-focality were detected in untreated and treated mice. Ninety-three percent (1,174/1,258) of tumors had the solid growth pattern widely reported in this model. However, among the solid tumors, a spectrum of growth patterns, from well-circumscribed tumors with a pseudocapsule to locally invasive or highly aggressive, metastatic subtype, was observed. Of the non-solid tumors, glandular features were prominent in 84 (7%). Adenocarcinomas included papillary, acinar/glandular, and adenosquamous subtypes. Adenosquamous tumors were exclusively observed in the group of mice treated on a short-term basis with estrogen. In contrast to the reported literature for this transgenic mouse model, mammary tumors were multifocal in the majority of cases (303 of 417 mice, or 73%). Results of this extensive study of a single transgenic model of mammary tumorigenesis indicate phenotypic and biological heterogeneity not previously associated with this transgenic mouse. These data support a complex, multistep process of carcinogenesis and clonal evolution, with biological and phenotypic variance similar to that observed in human mammary cancer development.


Subject(s)
Genes, erbB-2 , Mammary Neoplasms, Animal/genetics , Mammary Tumor Virus, Mouse/genetics , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Animals , Diet , Female , Mammary Neoplasms, Animal/pathology , Mice , Mice, Inbred Strains , Mice, Transgenic
3.
Cancer Res ; 63(10): 2425-33, 2003 May 15.
Article in English | MEDLINE | ID: mdl-12750262

ABSTRACT

Exogenous and dietary estrogens have been associated with modification of breast cancer risk. Mammary cancer model systems can be used to explore interactions between specific transgenes, and hormonal and dietary factors. Transgenic mice bearing the rat wild-type erbB-2 gene were used to study the effects of short-term hormonal exposure [17beta-estradiol (E2) or tamoxifen] or a soy meal diet on mammary carcinogenesis. In mice fed a casein diet, mammary tumors developed at an earlier age after short-term E2 exposure during the early reproductive period. The median mammary tumor latency was shortest (29 weeks) for the high-dose estrogen as compared with the lowest dose of E2 treated or placebo control mice (33 and 37 weeks, respectively). The timing of short-term E2 exposure was also important, with the most significant changes observed in mice exposed to E2 between 8 and 18 weeks of age. E2 exposure was associated with the subsequent development of more aggressive tumors as determined by histologic grade, multifocal tumor development, stromal invasion, and pulmonary metastasis. In contrast, short-term tamoxifen-exposed mice generally failed to develop mammary tumors by 60 weeks of age. Mice fed a soy meal diet developed mammary tumors at a later age than casein-fed animals treated with E2 or placebo, whereas no differences were observed by diet for the tamoxifen-treated mice. Mammary tumor prevention was >80% in tamoxifen-treated mice on either diet. Novel histologic tumor types were identified, suggesting greater phenotypic diversity than described previously. Benign mammary gland morphogenesis was also significantly altered by short-term hormonal exposure or dietary factors, consistent with the modification of mammary tumor risk in specific treatment groups. Estrogenic modulation of the mammary tumor phenotype in wild-type erbB-2 transgenic mice was observed. Histologic tumor types and clinical aggressivity not reported previously in this transgenic model were noted, suggesting greater biologic heterogeneity than reported previously. In addition, dietary phytoestrogens modified mammary development and tumor latency, suggesting a need for greater stringency in dietary assignment for transgenic mouse models of mammary neoplasia.


Subject(s)
Cocarcinogenesis , Diet , Estradiol/pharmacology , Genes, erbB-2/genetics , Isoflavones , Mammary Neoplasms, Experimental/etiology , Tamoxifen/pharmacology , Age Factors , Animals , Anticarcinogenic Agents/adverse effects , Anticarcinogenic Agents/pharmacology , Disease Models, Animal , Estradiol/adverse effects , Estradiol/blood , Estrogen Antagonists/adverse effects , Estrogen Antagonists/pharmacology , Estrogens, Non-Steroidal/pharmacology , Female , Mammary Glands, Animal/drug effects , Mammary Glands, Animal/growth & development , Mammary Neoplasms, Experimental/chemically induced , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/prevention & control , Mammary Tumor Virus, Mouse/genetics , Mice , Mice, Transgenic , Phytoestrogens , Plant Preparations , Risk Factors , Tamoxifen/adverse effects
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