title: Requirement for BUB1B/BUBR1 in tumor progression of lung adenocarcinoma.
abstract: Lung adenocarcinoma is often discovered as metastatic disease with very poor prognosis. However, much remains unknown about the mechanisms of lung adenocarcinoma tumor progression. In this study we showed that knockdown of BUB1B/BUBR1, a critical mitotic checkpoint protein, significantly inhibited anchorage-independent growth of lung adenocarcinoma cell lines. In allograft and tail vein mouse model studies, BUB1B suppression inhibited primary tumor growth and reduced metastasis to the lung and lymph nodes, resulting in prolonged survival in both tumor prevention and tumor intervention settings. Mechanistic studies revealed that BUB1B knockdown sensitized cells to anoikis. The N-terminal region and GLEBS domain of BUB1B were required for its functions in both anchorage-independent growth and anoikis resistance, whereas the kinase domain was less critical. Overexpression of BUB1B is associated with disease progression and poor survival in human lung adenocarcinoma patients. Collectively, these data reveal a novel function for BUB1B in mediating anchorage-independent survival and growth, thereby facilitating lung adenocarcinoma dissemination during metastasis. Thus, targeting BUB1B could provide potential therapeutic benefit in suppressing metastasis and prolonging survival in lung adenocarcinoma patients.
authors.affiliation: Departments of Molecular Biology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Honglin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Discovery Oncology, Genentech Inc., South San Francisco, California, USA.
authors.forename: James
authors.initials: J
authors.lastname: Lee
authors.affiliation: Molecular Oncology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Noelyn M
authors.initials: NM
authors.lastname: Kljavin
authors.affiliation: Departments of Molecular Biology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haley
authors.affiliation: Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Daemen
authors.affiliation: Discovery Oncology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Leisa
authors.initials: L
authors.lastname: Johnson
authors.affiliation: Departments of Molecular Biology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Liang
keywords: BUB1B/BUBR1; anchorage-independent growth; anoikis; lung adenocarcinoma; metastasis