Immunolocalisation of Key Spindle Assembly Checkpoint Proteins – Correlation with Cellular Prolifaration and Chemotherapeutic Response
SM Phelan, B McGrogan, M Prencipe, P Fitzpatrick, D Brennan, C O'Herlihy, M Foley, E Doyle, J Harford, T O'Grady, E Kay. University College Dublin, Dublin, Ireland; National Maternity Hospital, Holles St., Dublin, Ireland; St. Vincent's University Hosptial, Dublin, Ireland; Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
Background: Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy, often presenting at an advanced stage. Treatment for EOC is hampered by high levels of intrinsic and acquired drug resistance. The taxanes are microtubule stabilizing agents, used as first-line agents in the treatment of EOC. The spindle assembly checkpoint (SAC) is a regulatory mechanism, preventing chromosome segregation during mitosis. It forms the molecular machinery through which the taxanes exert their effect. Studies analyzing the immunohistochemical localization of these markers in clinical material are limited. BUBR1 transcription is controlled by p53 and silencing of BUBR1 reduces phosphorylation and stability of p53, with higher levels of BUBR1-p53 interaction in mitotic cells. Overexpression of BUBR1 and MAD2, have been associated with high cellular proliferation, as measured by Ki-67 expression, in a number of human tissues but this has not been studied in EOC.
Design: We performed IHC for BUBR1, MAD2, Ki-67 and p53 on a tissue microarray (TMA) constructed from a cohort of EOC (n=61), including a variety of histological subtypes, in order to characterize the immunolocalisation patterns of key SAC proteins in EOC.
Results: Both of the SAC proteins, MAD2 and BUBR1 were overexpressed in this tumour type, with cytoplasmic and nuclear staining patterns observed. Cytoplasmic BUBR1 and nuclear MAD2 both associated with cellular proliferation in our cohort (p=0.009, p=0.008 respectively). Importantly, increased nuclear MAD2 expression was associated with an improved response to combined platinum-taxane based chemotherapy (p=0.044).
Conclusions: Both BUBR1 and MAD2 are commonly overexpressed in EOC, with MAD2 most commonly localizing to the nucleus and BUBR1 to the cytoplasm in this tumour type. BUBR1 did not associate with treatment response, however tumours with strong nuclear MAD2 expression showed a significant association with a positive response to chemotherapy and this may be a useful marker in predicting patient response in the future.
Category: Gynecologic & Obstetrics
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 168, Wednesday Afternoon