Mechanism of cytokinesis failure in ovarian cystadenomas with defective BRCA1 and P53 pathways. Issue 11 (3rd October 2018)

• Record Type: Journal Article
• Authors: Austria, Theresa; Marion, Christine; Yu, Vanessa; Widschwendter, Martin; Hinton, David R.; Dubeau, Louis
• Is Part Of: International journal of cancer. Volume 143:Issue 11(2018)
• Page Start: 2932
• Page End: 2942
• Publication Date: 2018-10-03
• Subjects: ovarian carcinoma -- aneuploidy -- BRCA1 -- cytokinesis failure -- P53; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31659
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : We previously described an in vitro model in which serous ovarian cystadenomas were transfected with SV40 large T antigen, resulting in loss of RB and P53 functions and thus mimicking genetic defects present in early high‐grade serous extra‐uterine Müllerian (traditionally called high‐grade serous ovarian) carcinomas including those associated with the BRCA1 mutation carrier state. We showed that replicative aging in this cell culture model leads to a mitotic arrest at the spindle assembly checkpoint. Here we show that this arrest is due to a reduction in microtubule anchoring that coincides with decreased expression of the BUB1 kinase and of the phosphorylated form of its substrate, BUB3. The ensuing prolonged mitotic arrest leads to cohesion fatigue resulting in cell death or, in cells that recover from this arrest, in cytokinesis failure and polyploidy. Down‐regulation of BRCA1 to levels similar to those present in BRCA1 mutation carriers leads to increased and uncontrolled microtubule anchoring to the kinetochore resulting in overcoming the spindle assembly checkpoint. Progression to anaphase under those conditions is associated with formation of chromatin bridges between chromosomal plates due to abnormal attachments to the kinetochore, significantly increasing the risk of cytokinesis failure. The dependence of this scenario on accelerated replicative aging can, at least in part, account for the site specificity of the cancers associated with the BRCA1 mutation carrier state, as epithelia of the mammary gland and of the reproductive tract are targets of cell‐nonautonomous consequences of this carrier state on cellular proliferation associated with menstrual cycle progressions. Abstract : What's new? Decreased BRCA1 expression, a hallmark of BRCA1 ‐mutated cancers, is associated with increased polyploidy and elevated risk of aneuploidy and malignant transformation. Here, in cultures of serous ovarian cystadenomas, BRCA1 silencing led to uncontrolled microtubule anchoring to the kinetochore, which was overcome by chromosome bridging and cytokinesis failure, thereby increasing polyploidy risk. Experiments in aging ovarian cystadenomas indicate that reduced microtubule anchoring and spindle assembly checkpoint arrest are coincident with decreased expression of BUB1 kinase and its phosphorylated substrate BUB3. The findings provide insight into aneuploidy mechanisms in BRCA1 ‐mutated malignancies, which could aid progress in early detection of precursor lesions.