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Abstract
Abstract We have previously shown that BAG3 is a pro-survival protein in human cancer lines subject to stress. BAG3 overexpression also mediates a decrease in migration and adhesion to matrix in MDA-435 breast cancer cells; this is reversed in a BAG3 mutant with a deleted proline-rich domain (PXXP). Additionally, BAG3 induces the secreted molecule CCN-1 to regulate in vitro invasion of HeLa cells. This led us to hypothesize that MMTV-driven human BAG3 would contribute to mammary tumorigenesis. This was examined through generation and analysis of a transgenic mouse model of human BAG3 ectopically expressed under the MMTV promoter in FVB/N mice. Five of 14 confirmed founder lines were selected for characterization to rule out integration effects. Each line was shown to express hBAG3 in mammary ductal epithelium, a typical feature of the MMTV-driven transgenes. We next applied chemical carcinogenesis with DMBA (7,12-dimethylbenzanthracene) to eight-week old virgin transgenic females and age-matched FVB/N wild-type females, by weekly orogastric gavage (1 mg DMBA) for 6 weeks. At study end (18 weeks post DMBA-treatment), 5/19 (26%) transgenic animals had pathologically proven atypical hyperplasia [1], and malignant tumors [adenocarcinoma, 1; myoepithelial tumor, 2; adenosquamous carcinoma, 1]. The age-matched non-transgenic controls did not develop premalignant or malignant breast lesions [0/12]. Luminal cell expression of hBAG3 was present in the atypical hyperplasia, but was not observed in highly proliferative, less differentiated regions of tumors where ductal structures are absent. Since the tumors we obtained were both of the myoepithelial and the epithelial lineages, we next investigated whether forced expression of hBAG3 in the ductal epithelium may dysregulate mammary gland development. We collected mammary glands at 5, 7, 10, and 13 weeks of age from transgenic and wild-type animals (n=4 each per time point) for two selected MMTV-hBAG3 transgenic lines. The terminal end buds, epithelial elongation, and glandular differentiation are currently being analyzed. Our preliminary data indicate that the mammary gland of MMTV-hBAG3 mice have a trend to increased epithelial elongation and more secondary acinar structures in the later pubertal stages. A complete analysis of the study cohort will be discussed. The effects of multiple pregnancies and post-lactation involution are under study. Together our findings point to a putative role of BAG3 as contributor to mammary remodeling during puberty and a promoting effect during chemical carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2388. doi:10.1158/1538-7445.AM2011-2388
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