Abstract
Abstract Despite treatment advances, breast cancer remains the second most lethal malignant disease for women worldwide. Although pharmacologic agents that modulate estrogen receptor-alpha (ER) functions or reduce circulating estrogens levels significantly reduced mortality in patients with estrogen sensitive (ER positive) tumors, both de novo and acquired resistance limits efficacy. A critical need for identifying more precise diagnostic/prognostic biomarkers and novel therapeutic targets prompted deeper investigation into ER-coregulatory protein function and regulation. ER-coactivator PELP1, mediates both nuclear and extra-nuclear estrogen signaling and crosstalk with growth factors. Deregulated PELP1 expression occurs in hormone-driven cancers, associates with undifferentiated invasive breast adenocarcinomas and an independent prognostic biomarker in assessing clinical outcome of luminal-like breast cancer patients. Collectively, several studies suggest PELP1 is an ER coregulator with tumorigenic potential. However, the in vivo significance of PELP1 deregulation during initiation and progression of breast cancer remains unknown. To determine the role of PELP1 over-expression in mammary tumorigenesis, we generated an inducible transgenic murine model. Transgene construct (pTetOPELP1) consists of a full-length human PELP1 cDNA linked to luciferase gene reporter through an internal ribosomal entry site (IRES). pTetOPELP1 mice crossed with mammary gland-specific rtTA mice (MMTVrtTA) to establish two independent MMTVrtTA-TetOPELP1 transgenic lines. Transgene induction in adult nulliparous bitransgenic females was achieved with doxycycline administered in drinking water. Concurrent expression and activity of the luciferase gene reporter was detected specifically in the mammary gland by in vivo bioluminescence imaging, luciferase assay and RT-PCR. Mammary epithelial-specific expression of PELP1 was validated by immunohistochemistry and Western blot analysis. PELP1-mediated morphological and histological changes were analyzed by examining carmine-stained whole mounts and H&E-stained paraffin embedded mammary glands sections. We observed an increase in proliferation, extensive side branching and precocious differentiation in PELP1 expressing mammary gland compared to controls. Aged MMTVrtTA-TetOPELP1 bitransgenic mice (n=42) revealed hyperplasia and preneoplastic changes as early as 12 weeks with ER-positive mammary gland tumors developing by 8 months following PELP1 induction. Taken together, we established PELP1 as an oncogenic in vivo. Our inducible mammary-specific PELP1 transgenic model will serve as a valuable tool for future in vivo investigation into molecular mechanisms of PELP1-mediated tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3294. doi:1538-7445.AM2012-3294
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