ATP binding cassette transporters and drug resistance in breast cancer.

Abstract

Resistance to chemotherapy is a critical issue in the management of breast cancer patients. The nature of clinical drug resistance is likely to be multifactorial. However, in the last decade considerable attention has been dedicated to the role played by membrane transporter proteins belonging to the ATP binding cassette protein superfamily, and in particular by the MDR1 product P-glycoprotein (Pgp) and the multidrug resistance protein (MRP1). Heterogeneity of results is a common feature of studies evaluating the expression and prognostic role of these proteins, due to both methodological and biological factors. Nonetheless, Pgp and MRP1 are detected in a significant proportion of untreated breast cancers (on average 40 and 50% respectively, by immunohistochemistry), without a clear and consistent association with cancer stage. Exposure to chemotherapy increases the expression of both proteins. In vitro studies on primary cultures of breast cancer cells obtained at surgery consistently show an association between Pgp (protein) or MDR1 (mRNA) expression and resistance to chemotherapy. However, the correlation with clinical drug resistance is not as well defined. A stronger association of Pgp/MDR1 with response rates has been observed when expression or an increase in expression are detected immediately following chemotherapy. Correlations with prognosis appear more evident in studies using immunohistochemistry, in adjuvant and neoadjuvant settings. Evidence of clinical reversal of drug resistance by verapamil suggests a functional role of Pgp in drug resistance, although the significance of the evidence is generally weakened by poor trial designs. Future studies should take into account the multifactorial nature of drug resistance in breast cancer and use standardized approaches with adequate controls. Expression studies should be complemented by well-designed trials of drug-resistance reversal using target-specific chemosensitizing agents, and relating the results to the levels of expression of the target proteins.

Prognostic impact of multidrug resistance gene expression on the management of breast cancer in the context of adjuvant therapy based on a series of 171 patients

“…However, very limited data are available in the literature in this field and the precise mechanism of action, the relationship between multidrug resistance genes, and their clinical impact on the outcome of patients with breast cancer remain unclear, as published results have been discordant (Keith et al, 1990;Buser et al, 1997;Frassoldati et al, 1997;Silvestrini et al, 1997;Trock et al, 1997;Ferrero et al, 2000;Leonessa and Clarke, 2003). Few data are available concerning the impact of multidrug resistance genes on the clinical outcome of patients treated for breast cancer.…”

“…In a study of 27 patients, the risk of relapse in the 10 years following adjuvant chemotherapy was higher in patients whose primary tumours expressed higher levels of MRP1 mRNA (Ito et al, 1998). Heterogeneous results are a common feature of studies evaluating the expression and prognostic role of this gene, mainly due to both methodological and biological factors, and the prognostic impact of these two genes on DFS or OS remains to be established (Leonessa and Clarke, 2003).…”

“…In humans, P-glycoprotein (P-gp), encoded by the multidrug resistance gene 1 gene (MDR1) (Endicott and Ling, 1989;Gottesman and Pastan, 1993), and multidrug resistance-related protein MRP1, first described by Cole et al (1994), are two membrane glycoprotein transporters belonging to the more extensive superfamily of ATP-binding cassette (ABC) proteins (Dean et al, 2001). More recently, other members of this family have been implicated in multidrug resistance of breast cancer, such as BCRP/ABCG2 and other forms (Leonessa and Clarke, 2003). Such proteins act as energy-dependent efflux pumps capable of expelling a large range of xenobiotics, including doxorubicin and other cytotoxic drugs derived from natural products, out of the cell.…”

Multidrug Resistance Mediated by MRP1 Gene Overexpression in Breast Cancer Patients

“…It was strongly suggested that expression of MRP1 gene is responsible for a negative response in early breast cancer and thus MRP1 gene expression levels can be used as marker for breast cancer (17). Leonessa et al have shown that early expression of MRP1 is directly correlated with a worse prognosis (18) while Trock et al demonstrated that MRP1 gene expression was in low levels before chemotherapy in breast cancer samples as compared to the samples after chemotherapy (19).…”

A Synergistic Interaction between Lapatinib and Chemotherapy Agents in a Panel of Cell Lines Is Due to the Inhibition of the Efflux Pump BCRP

“…They are also expressed in cancer tissues and are important in determining resistance to specific chemotherapy agents such as the taxanes and topoisomerase inhibitors (13). Drug efflux is largely mediated by the ATP-binding cassette (ABC) transporters p-glycoprotein (P-gp) ABCB1 and breast cancer-related protein (BCRP) ABCG2.…”