Deregulated estrogen receptor alpha expression in mammary epithelial cells of transgenic mice results in the development of ductal carcinoma in situ - PubMed (original) (raw)

. 2005 Feb 1;65(3):681-5.

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Deregulated estrogen receptor alpha expression in mammary epithelial cells of transgenic mice results in the development of ductal carcinoma in situ

M Silvina Frech et al. Cancer Res. 2005.

Abstract

A conditional tetracycline-responsive transgenic mouse model with deregulated estrogen receptor alpha expression in mammary epithelial cells developed ductal hyperplasia (DH), lobular hyperplasia, and ductal carcinoma in situ (DCIS) by 4 months of age. Higher proliferative rates were found in both normal and abnormal ductal and lobular structures. DH and DCIS but not normal ductal structures showed an increased percentage of cells with nuclear-localized cyclin D1. No differences in either the prevalence or extent of these phenotypes following exogenous 17beta-estradiol treatment were found suggesting that alteration of ERalpha expression was the rate-limiting factor in initiation of DH, lobular hyperplasia, and DCIS.

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Figures

Figure 1.

Figure 1.

Immunohistochemical detection of ERα in the mammary epithelial cells of control (_A_-B) and CERM mice (_C_-F) following exposure to either placebo (A, C, and E) or 17β-estradiol (B, D, and F). The mean percentage of mammary epithelial cells showing nuclear-localized ERα expression was significantly lower in 17β-estradiol exposed control mice (B) as compared with placebo-treated control mice (A). CERM mice showed a higher mean percentage of mammary epithelial cells with nuclear-localized ERα expression (C and D) than control mice in both the placebo- and 17β-estradiol-treated groups. The mean percentage of mammary epithelial cells demonstrating nuclear-localized ERα expression in the DHs found in the CERM mice was similar in placebo-treated (E) and 17β-estradiol-treated mice (F). Arrows nuclear-localized ERα. Bar, 20 μm.

Figure 2.

Figure 2.

Mammary gland whole mounts with representative normal mammary ductal structure in control mice treated with 17β-estradiol (B) and the presence of abnormal secondary and tertiary branching (black arrows, A, and C), dilated ducts (dashed arrows, C, and D), and lateral budding (arrowhead, D) in CERM mice. Mammary gland whole mounts from 2-month-old ovariectomized mice (I) and 12-month-old CERM mice (thin black arrow, hyperplastic alveolar nodule, J). H&E-stained sections of mammary tissue from CERM mice show DCIS (E, F, G, and H). There were no structural differences found between placebo treated and 17β-estradiol exposed CERM mice. White arrows, mitotic figures (E and G). Bar, 200 μm(A, B, C, D, I, and J). Bar, 20 μm (E, F, G, and H).

Figure 3.

Figure 3.

Immunohistochemical detection of PCNA (A, C, E, and G) and cyclin D1 (B, D, F, and H) in mammary epithelial cells of control (_A_-B) and CERM mice (_C_-H). There was an increase in the mean percentage of mammary ductal epithelial cells that showed nuclear-localized PCNA in CERM (C, E, and G) as compared with control (A) mice (P ≤ 0.05; ANOVA, Bonferroni’s test). The mean percentage of cells demonstrating nuclear-localized PCNA (arrows) was not significantly different between the normal-appearing ducts (C), LH (E), and DH and DCIS (G). The mean percentage of mammary epithelial cells demonstrating nuclear-localized cyclin D1 in normal appearing ducts was not increased in CERM (D) as compared with control (B) mice. In contrast, the mean percentage of mammary epithelial cells demonstrating nuclear-localized cyclin D1 in DH and DCIS (H, arrows) was significantly increased as compared with normal appearing ducts of CERM (P ≤ 0.05) and normal ducts of control mice (P ≤ 0.01; ANOVA, Bonferroni’s test). Bar, 20 μm.

Figure 4.

Figure 4.

Immunohistochemical detection of ERα (A), cyclin D1 (B), PR (C), Ki67 (D), PCNA (E), and p27 (F) in a single DCIS lesion from a 4-month-old nulliparous placebo-treated CERM mouse. Arrows, representative cells demonstrating nuclear-localized protein. Bar, 20 μm.

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