Novel mouse model for studying role of ER-nongenomic actions in breast cancer.

Abstract

#601 Back ground: Estradiol (E2) and estrogen receptor (ER) signaling play a key role in development and progression of breast cancer. ER signaling is complex, involves coregulatory proteins and the status of ER coregulators in tumor cells plays an important role in hormonal responsiveness and tumor progression. In addition, ER also participates in non-genomic signaling events in the cytoplasm, however the significance of non-genomic signaling in mammary tumorigenesis remain unknown. PELP1/MNAR is novel ER coregulator that participates in ER genomic and non-genomic actions. PELP1 expression is deregulated in breast tumors and in a subset of tumors PELP1 is predominantly localized in the cytoplasm. Since PELP1 cytoplamsic localization promotes excessive activation of Src and AKT pathways, we hypothesized that PELP1 mediated excessive activation of ER-nongenomic functions may play a role tumorigenesis. To test this, we have generated MMTV-PELP1cyto TG model that uniquely express PELP1 in the cytoplasm of mammary glands that mimics the pathological situation of PELP1 localization seen breast cancer.
 Methods: As a means of targeting the expression of the PELP1 transgene to the mammary gland, we placed the PELP1cyto cDNA under the control of the MMTV promoter. PELP1 transgene integration was verified by PCR and expression levels by Western and IHC in each founder line. Whole-mount preparations and IHC analysis was performed using Tg and age controlled wild type littermates from different developmental stages. Total protein extracts of mammary gland were used for western blot analysis of nongenomic signaling components.
 Results: Preliminary analysis of mammary gland from PELP-cyto mice showed hyperplasia, increased proliferation as analyzed by PCNA staining. Mammary tumors were observed as early as 32 weeks. No spontaneous mammary tumors were found in the wild type cohort. Pathological analysis revealed that these tumor masses represent full blown mammary adenocarcinomas. Mammary tumors showed excessive activation of nongenomic signaling including activation of Src and AKT pathways. A clear induction of aromatase expression was found in PELP1 tumors compared with the wild-type that showed no aromatase expression in the mammary gland.
 Discussion: We have established and characterized a transgenic mouse model that mimics deregulated ER-nongenomic signaling. Our results suggest that PELP1 is a proto-oncogene and demonstrates its in vivo tumorigenic potential. PELP1 driven tumors are ER+ve, express aromatase, thus provide an interesting in vivo model for studying ER-mediated tumorigenesis and to study effect of local E2 on ER-mediated tumorigenesis. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 601.