The role of efflux pumps in drug-resistant metastatic breast cancer: new insights and treatment strategies.

Abstract

Chemotherapy plays a vital role in the treatment and management of breast cancer and is associated with significant improvements in survival. Regimens such as CMF (cyclophosphamide/methotrexate/5-fluorouracil) and, more recently, TAC (docetaxel/doxorubicin/cyclophosphamide) have been used with good response rates and complete remissions achieved in approximately 15% of cases. However, a significant proportion of women experience a recurrence of metastatic disease, with an average survival between 1-2 years. The monoclonal antibody trastuzumab is used in the treatment of HER2/neu-positive breast cancer. Although such targeted agents have heralded an exciting new era in cancer therapy, they are limited by the fact that only a subset of patients can benefit from treatment and by the emergence of resistance. Thus, the pursuit of a strategy that modulates resistance to standard chemotherapeutics remains valid. Accumulating evidence indicates that a number of mechanisms known to contribute to clinical drug resistance might be relevant to breast cancer. Tumor cell drug resistance might arise as a result of systemic pharmacologic factors, changes in the tumor microenvironment (eg, pH), cellular pharmacokinetics, drug metabolism and detoxification, drug target modifications, DNA repair, and apoptotic mechanisms. The adenotriphosphate-binding cassette membrane transporter family contributes to clinical drug resistance, especially in breast cancer. The most frequently described of this family is P-glycoprotein, followed by multidrug resistance protein-1. This review describes the factors thought to play a role in clinical breast cancer drug resistance and describes potential methods by which it might be circumvented.

• Authors: Tito Fojo, Helen M Coley
• Journal: Clinical breast cancer (Clin Breast Cancer) Vol. 7 Issue 10 Pg. 749-56 (Oct 2007) ISSN: 1526-8209 [Print] United States
• PMID: 18021475 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Multidrug Resistance-Associated Proteins

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Antineoplastic Agents (metabolism, therapeutic use)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Drug Resistance, Neoplasm (physiology)
• Female
• Humans
• Multidrug Resistance-Associated Proteins (metabolism)