MHOR002 expression: Forkhead box O transcription factors both suppress and support breast cancer progression.

FOXOs are regulators of cellular homeostasis and putative tumor suppressors. The role of FOXOs in cancer progression remains to be determined however as the data on FOXO function in cancer are fragmentary and come from studies that focused on isolated aspects of cancer, especially for epithelial cancers. To clarify the role of FOXOs in epithelial cancer progression we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Strikingly, either activation or loss of FOXO function suppresses tumor growth and metastasis. We show that the multitude of cellular processes critically affected by FOXO function including proliferation, survival, redox homeostasis and PI3K-signaling need to be carefully balanced for tumor cells to thrive. Mouse invasive lobular carcinoma cells mILC1 were derived from tumors that developed in female K14cre;Cdh1F/F;Trp53F/F mice. In these cells Foxo1 and Foxo3 knockdown was done using the lentiviral FH1tUTG doxycycline inducible vector. Resulting mILC1-shFOXOs cells were treated with and without Doxycyclin for 48hr and 72hr. pINDUCER20-GFP-FOXO3mt was used for induction of mutant FOXO3.A3 in the same parental cells. mILC1-iFOXO3.A3 cells were induced with and without Doxycyclin for 8hr and 16hr. Four independent samples for each condition were hybridized against a common-reference sample of the parental mILC1 cells in balanced dye-swap design. Microarrays used were Agilent Mouse WHole Genome Expression arrays V1 (44K).