Abstract 3397: The role of Pdef in mammary development, tumorigenesis and metastasis

Abstract

ETS proteins represent one of the largest families of transcription factors with diverse functions that activate or repress the expression of genes that are involved in various biological processes, including cellular proliferation, differentiation, development, transformation and apoptosis. The ETS family gene, PDEF (prostate derived ets factor), is expressed in normal epithelial tissues including prostate, breast, colon and bladder. Significantly, PDEF protein is present in non-invasive cancers but reduced or absent in most invasive cancers. By re-expression and knock-down of PDEF in cancer cell lines, we and others have shown that PDEF target genes control aspects of the metastatic process, including cell growth, migration and invasion. We hypothesize that PDEF is important for normal developmental processes and that loss of PDEF regulatory networks is a key event in the development of invasive cancer. To study the function of Pdef in vivo, we generated mice with constitutive Pdef knockout (Pdef −/−). Specific stages of mammary development were examined, including early-pubescent (5 week), virgin adult (8 week), pregnancy (days 7.5 and 13.5), lactation (days 1 and 7) and involution (day 7). Inhibition of the development of the ductal tree and an increase in ductal side branching and terminal end bud proliferation was observed in 5-8 week old virgin Pdef −/− mice. TGFβ1 and ERα are required for development of the ductal tree during puberty and mRNA levels for both are reduced in the Pdef −/− mice at 5 and 8 weeks of age. Incomplete lobuloalveoli development was observed in Pdef −/− pregnant and lactating mice, although no phenotypic effects were observed in the resultant pups. To explore the role of Pdef in mammary tumor progression and metastasis, we generated mice expressing the MMTV-PyMT or MMTV-Neu oncogene in wild type and Pdef −/− backgrounds. No impact of Pdef dosage upon tumor incidence or growth was observed in the PyMT model; however, initial tumor formation was delayed by 4 weeks (8.9 vs. 4.8) and time from tumor initiation to sacrifice was 3 weeks longer (29.4 vs 26.4) in the Pdef −/− Neu model. Significantly, an increase in lung metastasis was observed in the Pdef −/− mice in both the PyMT and Neu models. Thus, loss of Pdef in vivo is associated with defects in mammary development and increased metastasis in mouse models of breast cancer, suggesting Pdef is a metastasis suppressor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3397.