Proteomic identification of putative biomarkers of neo-adjuvant chemotherapy resistance in luminal (ER+) breast cancer

Hussain, Tasadooq

November 2013

Thesis or dissertation

© 2013 Tasadooq Hussain. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

Neoadjuvant chemotherapy is a standard treatment for locally advanced breast cancer however chemoresistance can be a major obstacle in ER+ cancers. Using comparative proteomic approaches (antibody microarray/AbMA and 2D-PAGE with MALDI-TOF/TOF MS) to investigate a pilot series of breast cancer samples our research group recently identified 14-3-3 theta/tau, tBID and BcL-XL as putative biomarkers of response to neoadjuvant chemotherapy (Hodgkinson et al J Prot 2012, 75:1276-1283 and 75:2745-2752). Here we aimed to analyse further samples using the AbMA approach and to re-analyse the combined data.

Samples from chemoresistant and chemosensitive breast cancers were selected following anthracycline-taxane chemotherapy and 4 experiments were performed using ductal ER+ tumours. Differential protein expression was compared between chemoresistant and chemosensitive samples using the Panorama XPRESS Profiler725 AbMA kit. The combined data from 9 AbMA assays and 3 2D-PAGE/MS experiments was then analysed using Ingenuity Pathway Analysis (IPA; Ingenuity Systems). A pilot series of archival samples was used for clinical validation of putative predictive biomarkers.

89 differentially expressed proteins (DEPs) were seen in the 4 further AbMA experiments. In the combined dataset (12 experiments from 2 proteomic platforms), 8 DEPs were seen in at least 3 experiments. These were 14-3-3 theta, 14-3-3 epsilon, 14-3-3 gamma, Bcl-xl, Bid, Phosphokinase B, Vimentin and FAK. 121 DEPs from the combined data were analysed using IPA; 13 DEPs were mapped onto the PI3K/AKT pathway. Clinical validation in a pilot series of archival samples revealed AkT-1 Ser473 and FAKY397 alongside the previously identified and validated 14-3-3 theta/tau, and tBID to be significantly associated with chemotherapy resistance.

Conclusion: We have now identified at least 8 proteins which could play a role in breast chemoresistance. We propose a potential role for AkT-1, FAK, 14-3-3 theta/tau and tBID as predictive biomarkers of neoadjuvant chemotherapy resistance in breast cancer. Further validation in a larger sample series is now required.

Hull York Medical School, The University of Hull
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