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Author(s): McGrogan BT (McGrogan, Barbara T.); Gilmartin B (Gilmartin, Breege); Camey DN (Camey, Desmond N.); McCann A (McCann, Amanda)
Title: Taxanes, microtubules and chemoresistant breast cancer
Source: BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER 1785 (2): 96-132
Date: 2008 APR
Document Type: Journal : Review
DOI: 10.1016/j.bbcan.2007.10.004
Language: English
Comment:
Address: Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland.
Univ Coll Dublin, UCD Sch Med & Med Sci SMMS, Dublin 4, Ireland. Mater Misericordiae Univ Hosp, Dublin 7, Ireland. Reprint: McCann, A, Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4,
Ireland. E-mail: amanda.mccann@ucd.ie
Author Keywords: breast cancer; taxanes; microtubules; chemoresistance; spindle assembly
checkpoint (SAC); tubulin; BRCA1; mitotic assembly deficient protein 2
(MAD2)
KeyWords Plus: SPINDLE-ASSEMBLY CHECKPOINT; HUMAN OVARIAN-CANCER; CELL LUNG-CANCER;
BETA-TUBULIN GENE; NF-KAPPA-B; TAXOL-INDUCED APOPTOSIS; CHEMOTHERAPY-
INDUCED APOPTOSIS; PACLITAXEL-INDUCED APOPTOSIS; ACTIVATED PROTEIN-
KINASE; SURGICAL ADJUVANT BREAST
Abstract: . The taxanes, paclitaxel and docetaxel are microtubule-stabilizing agents that function primarily by interfering with spindle microtubule dynamics causing cell cycle arrest and apoptosis. However, the mechanisms underlying their action have yet to be fully elucidated. These agents have become widely recognized as active chemotherapeutic agents in the treatment of metastatic breast cancer and early-stage breast cancer with benefits gained in terms of overall survival (OS) and disease-free survival (DFS). However, even with response to taxane treatment the time to progression (TTP) is relatively short, prolonging life for a matter of months, with studies showing that patients treated with taxanes eventually relapse. This review focuses on chemoresistance to taxane treatment particularly in relation to the spindle assembly checkpoint (SAC) and dysfunctional regulation of apoptotic signaling. Since spindle microtubules are the primary drug targets for taxanes, important SAC proteins such as MAD2, BUBR1, Synuclein-gamma and Aurora A have emerged as potentially important predictive markers of taxane resistance, as have specific checkpoint proteins such as BRCA1. Moreover, overexpression of the drug efflux pump MDR-1/P-gp, altered expression of microtubule-associated proteins (MAPs) including tau, stathmin and MAP4 may help to identify those patients who are most at risk of recurrence and those patients most likely to benefit from taxane treatment. (C) 2007 Elsevier B.V All rights reserved.
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