Title:Chemotherapy Resistance in Breast Cancer
VOLUME: 11 ISSUE: 4
Author(s):Polly Niravath and Julie Nangia
Affiliation:Baylor College of Medicine, DF Medline One Baylor Plaza, BCM 600, Honstonitx 77030.
Keywords:Breast cancer, chemotherapy, chemoresistance, taxane, anthracycline, platinum, antimetabolites.
Abstract:Chemoresistance is a major cause of breast cancer recurrence and
death. Currently, drug-resistant disease is treated by selection of another
drug(s), without understanding the molecular mechanism(s) involved in a
given patient’s chemoresistance. Better understanding of chemoresistance
may enable a more informed selection of chemotherapeutic agents and improve
patient outcomes.
The article reviews mechanisms of resistance to common chemotherapeutic agents in breast cancer: anthracyclines,
taxanes and antimetabolites. Gene amplification of YWHAZ, encoding an anti-apoptotic protein, and
LAPTM4B, encoding lysosomal-associated protein transmembrane 4B, decrease sensitivity to anthracyclines.
Overproduction of p-170 glycoprotein, encoded by MDR1 gene, pumps these drugs out of cancer cells. Overexpression
of topoisomerase II-alpha (TOP2A), which relaxes supercoiled DNA for replication, is associated
with more aggressive tumors. Taxanes paclitaxel and docetaxel bind beta-tubulin, disrupting microtubule stability,
causing cell cycle arrest and apoptosis. Taxane resistance is hypothesized to be due to increased tubulin
expression, altered expression of microtubule-associated proteins, alternative tubulin isoforms, or overexpression
of Tau protein which stabilizes microtubules. Overexpression of MDR1 gene and Pgp (permeability glycoprotein)
cause efflux of taxanes from cells.
Knockdown of YWHAZ and LAPTM4B genes in cell lines has increased sensitivity to anthracyclines. Overcoming
taxane resistance may employ microtubule-inhibiting agents not vulnerable to known mechanisms of
resistance, such as eribulin, which has been studied in the phase III EMBRACE clinical trial. Strategies to
overcome resistance to antimetabolites capecitabine and gemcitamine include: dose escalation, pharmacologic
manipulation of drug metabolism, and design of new antimetabolites. A clearer understanding of resistance
would enable developing more informed, rational treatment strategies than the current trial-and-error method.
