title: Spindle assembly checkpoint protein expression correlates with cellular proliferation and shorter time to recurrence in ovarian cancer.
abstract: Ovarian carcinoma (OC) is the most lethal of the gynecological malignancies, often presenting at an advanced stage. Treatment is hampered by high levels of drug resistance. The taxanes are microtubule stabilizing agents, used as first-line agents in the treatment of OC that exert their apoptotic effects through the spindle assembly checkpoint. BUB1-related protein kinase (BUBR1) and mitotic arrest deficient 2 (MAD2), essential spindle assembly checkpoint components, play a key role in response to taxanes. BUBR1, MAD2, and Ki-67 were assessed on an OC tissue microarray platform representing 72 OC tumors of varying histologic subtypes. Sixty-one of these patients received paclitaxel and platinum agents combined; 11 received platinum alone. Overall survival was available for all 72 patients, whereas recurrence-free survival (RFS) was available for 66 patients. Increased BUBR1 expression was seen in serous carcinomas, compared with other histologies (P = .03). Increased BUBR1 was significantly associated with tumors of advanced stage (P = .05). Increased MAD2 and BUBR1 expression also correlated with increased cellular proliferation (P < .0002 and P = .02, respectively). Reduced MAD2 nuclear intensity was associated with a shorter RFS (P = .03), in ovarian tumors of differing histologic subtype (n = 66). In this subgroup, for those women who received paclitaxel and platinum agents combined (n = 57), reduced MAD2 intensity also identified women with a shorter RFS (P < .007). For the entire cohort of patients, irrespective of histologic subtype or treatment, MAD2 nuclear intensity retained independent significance in a multivariate model, with tumors showing reduced nuclear MAD2 intensity identifying patients with a poorer RFS (P = .05).
authors.affiliation: UCD School of Medicine and Medical Science, University College Dublin, UCD, Belfield, Dublin 4, Ireland; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; National Cancer Control Programme, King's Inns House, Dublin 1, Ireland. Electronic address: Barbara.mc-grogan@ucdconnect.ie.
authors.forename: Barbara
authors.initials: B
authors.lastname: McGrogan
authors.affiliation: UCD School of Medicine and Medical Science, University College Dublin, UCD, Belfield, Dublin 4, Ireland; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; Department of Histopathology, University Hospital Galway, Co. Galway, Ireland.
authors.forename: Sine
authors.initials: S
authors.lastname: Phelan
authors.affiliation: UCD School of Public Health, Physiotherapy & Population Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fitzpatrick
authors.affiliation: UCD School of Medicine and Medical Science, University College Dublin, UCD, Belfield, Dublin 4, Ireland.
authors.forename: Aoife
authors.initials: A
authors.lastname: Maguire
authors.affiliation: UCD School of Medicine and Medical Science, University College Dublin, UCD, Belfield, Dublin 4, Ireland; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Maria
authors.initials: M
authors.lastname: Prencipe
authors.affiliation: UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; National Maternity Hospital, Dublin 2, Ireland.
authors.forename: Donal
authors.initials: D
authors.lastname: Brennan
authors.affiliation: Rotunda Hospital, Dublin 1, Ireland.
authors.forename: Emma
authors.initials: E
authors.lastname: Doyle
authors.affiliation: Royal College of Surgeons in Ireland (RCSI) and Department of Histopathology, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Anthony
authors.initials: A
authors.lastname: O'Grady
authors.affiliation: Royal College of Surgeons in Ireland (RCSI) and Department of Histopathology, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Elaine
authors.initials: E
authors.lastname: Kay
authors.affiliation: School of Pharmacy, Queens University Belfast, Belfast, BT97BL, Northern Ireland, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Furlong
authors.affiliation: UCD School of Medicine and Medical Science, University College Dublin, UCD, Belfield, Dublin 4, Ireland; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Amanda
authors.initials: A
authors.lastname: McCann
mesh_terms: D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology*; D064246:Mad2 Proteins / Q000378:metabolism*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015996:Survival Rate; D013997:Time Factors
chemical_list: C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: BUB1-related protein kinase (BUBR1); Chemotherapeutic agents; Ki-67; Mitotic arrest deficient 2 (MAD2); Ovarian cancer; Recurrence-free survival (RFS); Spindle assembly checkpoint (SAC)