Identification of novel diagnostic and therapeutic factors for endocrine therapy-resistant breast cancer by next-generation sequencing strategy

2012-2012年度科学研究費助成事業(科学研究費補助金(若手研究(B))研究成果報告書 課題番号：24701033 研究代表者：伊地知暢広(鹿児島大学・大学院医歯学総合研究科・助教)本研究では、内分泌療法耐性乳がんの新規診断・治療分子標的の同定を目的とし、クロマチン免疫沈降法と次世代シーケンサーを活用してフォークヘッド転写因子FOXP1のゲノムワイドな結合領域の網羅的同定を行った。 エストロゲン刺激後のERα陽性乳がん細胞株MCF-7細胞において、約4000カ所超の結合領域を同定し、FOXP1がERα/FOXA1転写調節ネットワークに対し重要な役割を担っていることを明らかにした。さらに、タモキシフェン治療乳がん臨床検体を用いた免疫組織学的検討から、FOXP1がFOXA1と共にタモキシフェン治療乳がんの予後良好性を規定する因子であることを解明した。To identify the novel diagnostic and therapeutic factors for endocrine therapy-resistant breast cancer, we focused on FOXP1, one of a forkhead transcription factor family, as a candidate, and its genome-wide distribution in ER-positive breast cancer MCF-7 cells was examined by next-generation sequencing strategy. We demonstrated that majority of binding regions of FOXP1 in MCF-7 cells stimulated with estrogen were overlapped with those of both ER and FOXA1. We also demonstrated that the double-positive immunoreactivities of FOXP1 and FOXA1 are significantly associated with a favorable prognosis for survival of breast cancer patients receiving adjuvant tamoxifen therapy. In this study, we revealed that, similar to FOXA1, FOXP1 is assumed to be a critical transcription factor for ER signaling, and both forkhead transcription factors can serve as predictive factors for acquired endocrine resistance in breast cancer