Abstract B70: A conditional aromatase over-expressing in the mammary gland transgenic mouse as a potential model in cancer prevention research

Breast cancer develops as genetic changes accumulate in the ductal epithelium giving rise to precursor lesions such as atypical ductal hyperplasias, which may progress to ductal carcinoma in situ (DCIS) and eventually invasive breast cancer. This progress is promoted by estrogens. Estrogens are biosynthesized from androgens by the aromatase enzyme. Estrogen is required for the proliferation and morphogenesis of the normal mammary gland; however, studies suggest that estrogen and its metabolites may have mutagenic and carcinogenic potential in the mammary gland. Therefore, it is highly valuable to have mouse models with increased local estrogen production to use to develop optimal therapeutic and chemopreventive strategies to treat these lesions.

The purpose of this work is to develop a conditional transgenic mouse model that would provide an in vivo method of controlling the spatial and temporal regulation of aromatase expression.

The transgenic mouse model was developed by using two transgenes. One transgene is composed of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) linked to sequences encoding the tetracycline responsive reverse transactivator (rtTA). The other transgene has a tetracycline responsive promoter (tet-op) linked to sequences encoding the human aromatase (MMTV-rtTA/tet-op-Arom). Mammary glands were collected at 4 months of age for morphological, histological, and gene expression studies in both MMTV-rtTA/tet-op-Arom and wild-type mice.

RT-PCR analysis of aromatase mRNA shows that the gene is conditionally expressed in the mammary gland as compared to control mice. The mammary glands were evaluated for morphological changes using confocal microscopy, whole-mount and hematoxylin and eosin staining. Preliminary data at 4 months of age shows that overexpressing aromatase in the mammary gland leads to developmental abnormalities, abnormal ductal growth and increased ductal density. Gene expression studies will be performed to evaluate additional markers of proliferation, survival, and differentiation. This model is being cross-bred to our conditional overexpression of estrogen receptor α (ERα) in the mammary gland (CERM) model. CERM mice are an established tool for investigation of mechanisms involved in progression and regression of ERα-induced mammary hyperplasia and DCIS.

The novel CERM/tet-op-aromatase mouse model (CERM/Arom) is being developed to model more closely the human breast with expression of both ERα and aromatase in mammary tissue. This model can be utilized to evaluate agents to prevent carcinogenesis in the presence of aromatase over-expression in the mammary gland at specific times during development. This research is supported by the Susan G. Komen for the Cure Postodoctoral Fellowship Award KG080359 and the NIH National Cancer Institute Grant R01CA112176.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B70.