Rat strain-specific actions of 17β-estradiol in the mammary gland: Correlation between estrogen-induced lobuloalveolar hyperplasia and susceptibility to estrogen-induced mammary cancers

Abstract

The genetically related ACI and Copenhagen (COP) rat strains display diametrically opposed susceptibilities to mammary cancer development when treated chronically with 17␤-estradiol (E2). Here, we compare the actions of E2 on cell proliferation and lobuloalveolar development in the mammary glands of female ACI and COP rats. After 12 wk of E2 treatment, the mammary glands of ACI rats exhibited a significantly greater proliferative response to E2, compared with COP rats, as evidenced by quantification of S phase fraction and development of lobuloalveolar hyperplasia. Focal regions of atypical epithelial hyperplasia were observed in ACI, but not COP, rats. These strain differences were not because of differences in circulating E2, progesterone or, prolactin. Twothirds of the induced mammary cancers in ACI rats exhibited aneuploidy. The E2-induced mammary cancers regressed when hormone treatment was discontinued, indicating that they were estrogen-dependent. Progesterone receptor was expressed by the great majority of epithelial cells within the E2-induced atypical hyperplastic foci and the mammary carcinomas, suggesting a link between these lesions. These data demonstrate a correlation between E2 action in the induction of mammary cell proliferation and atypical epithelial hyperplasia and genetically conferred susceptibility to E2-induced mammary cancers. E pidemiologic studies suggest that estrogens are critical factors in breast cancer etiology (1-3). Supporting this link are the observations that early menarche, late menopause, late first full-term pregnancy, and nulliparity are each associated with increased risk of the disease, whereas oophorectomy prior to menopause significantly decreases breast cancer risk. A recent clinical trial demonstrated that the antiestrogen tamoxifen significantly reduces the incidence of breast cancer in women at high risk of developing the disease (4). One theory consistent with these data is that breast cancer risk is proportional to the cumulative number of ovulatory cycles and the repetitive stimulation of mammary cell proliferation by ovarian estrogens. At present, the molecular mechanisms through which estrogens contribute to the development of breast cancers are unknown.The ACI rat appears unique among rat strains in that it is highly susceptible to estrogen-induced mammary cancers but rarely develops mammary cancers spontaneously (5-15). We have demonstrated that chronic treatment with 17␤-estradiol (E2) induces mammary cancers in virtually 100% of ovary-intact ACI rats with a median latency of approximately 20 wk (15). In contrast, the Copenhagen (COP) rat is resistant to the development of estrogen-induced mammary cancers (5)(6)(7)(8)16). This difference between the ACI and COP rat strains is particularly striking because these strains are closely related genetically; the ACI strain was derived from a cross between the August and COP strains (17). Because the ACI and COP rat strains exhibit diametrically opposed susceptibilities to E2-induced mammary cancers (15, 16), the...

Heritable breast cancer in twins

“…When treated with estradiol at a standard dosage, certain rat strains rapidly develop breast cancer almost without exception (Shull et al, 1997;Harvell et al, 2000). Cancers resultant from a genetically induced enhancement of human sensitivity to hormone exposure would be induced by the first major endogenous hormone exposure at puberty, resulting in a pattern of risk like that observed among MZ twins (Table 1).…”

Haploid Inactivation of the Amplified-in-Breast Cancer 3 Coactivator Reduces the Inhibitory Effect of Peroxisome Proliferator-Activated Receptor γ and Retinoid X Receptor on Cell Proliferation and Accelerates Polyoma Middle-T Antigen-Induced Mammary Tumorigenesis in Mice

“…Because estrogen and ER␣ play an important role in hormonal promotion of mammary tumorigenesis (41,42) and AIB3 cellular concentrations have been shown to affect ER transcriptional activity in cultured cells (11)(12)(13), we compared ER␣ and its target gene expression in WT/PyMT and AIB3 ϩ/Ϫ /PyMT glands. Immunohistochemistry with ER␣-specific antibodies revealed no differences in ER␣ distribution pattern and immunoreactivity intensity between WT/ PyMT and AIB3 ϩ/Ϫ /PyMT glands, ductal hyperplasia, MIN, and tumors.…”

Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis

“…Chronic treatment with E 2 induces mammary cancer in 100% of ovary-intact ACI rats, with a median latency of 20 weeks (Harvell et al, 2000;Li et al, 2002a, b). Estrogen-induced mammary cancer is also accompanied by genomic instability in the form of loss of heterozygosity (Harvell et al, 2000;Li et al, 2002a).…”

“…Estrogen-induced mammary cancer is also accompanied by genomic instability in the form of loss of heterozygosity (Harvell et al, 2000;Li et al, 2002a). TAM has been shown to prevent ACI rat mammary gland tumor formation, and this effect appears to be mediated by the ER (Li et al, 2002b).…”

“…The choice of time points is based on when genomic instability (4 months) and mammary tumors (6 months) were first reported in these animals (Harvell et al, 2000;Li et al, 2002a, b). We observed increased ODD in the mammary gland of ACI rats after chronic E 2 treatment ( Figure 1a).…”