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.

Keywords: Breast cancer, chemotherapy, chemoresistance, taxane, anthracycline, platinum, antimetabolites.