Abstract
Three main xenobiotic efflux pumps have been implicated in modulating breast cancer chemotherapy responses. These are P-glycoprotein (Pgp), Multidrug Resistance-associated Protein 1 (MRP1), and Breast Cancer Resistance Protein (BCRP). We investigated expression of these proteins in breast cancers before and after neoadjuvant chemotherapy (NAC) to determine whether their levels define response to NAC or subsequent survival. Formalin-fixed paraffin-embedded tissues were collected representing matched pairs of core biopsy (pre-NAC) and surgical specimen (post-NAC) from 45 patients with invasive ductal carcinomas. NAC regimes were anthracyclines +/− taxanes. Immunohistochemistry was performed for Pgp, MRP1 and BCRP and expression was quantified objectively using computer-aided scoring. Pgp and MRP1 were significantly up-regulated after exposure to NAC (Wilcoxon signed-rank p = 0.0024 and p<0.0001), while BCRP showed more variation in response to NAC, with frequent up- (59% of cases) and down-regulation (41%) contributing to a lack of significant difference overall. Pre-NAC expression of all markers, and post-NAC expression of Pgp and MRP1 did not correlate with NAC response or with disease-free survival (DFS). Post-NAC expression of BCRP did not correlate with NAC response, but correlated significantly with DFS (Log rank p = 0.007), with longer DFS in patients with low post-NAC BCRP expression. In multivariate Cox regression analyses, post-NAC BCRP expression levels proved to predict DFS independently of standard prognostic factors, with high expression associated with a hazard ratio of 4.04 (95% confidence interval 1.3–12.2; p = 0.013). We conclude that NAC-induced expression levels of BCRP predict survival after NAC for breast cancer, while Pgp and MRP1 expression have little predictive value.
Highlights
Xenobiotic transporters are transmembrane efflux pumps that have protective physiological roles by removing potentially harmful molecules from the intracellular environment
Multidrug Resistance-associated Protein 1 (MRP1) is expressed in the vast majority of breast cancers as well as in some normal breast tissues, and high expression within breast tumours has generally been found to correlate with poor prognosis [4]
We examined expression levels of Pgp, MRP1 and Breast Cancer Resistance Protein (BCRP) in the tumours of 45 breast patients treated with neoadjuvant chemotherapy (NAC)
Summary
Xenobiotic transporters are transmembrane efflux pumps that have protective physiological roles by removing potentially harmful molecules from the intracellular environment These transporters can cause efflux of common chemotherapeutic agents and their activities have been implicated as mechanisms for therapy resistance in many cancer types. There are more than 30 individual human genes for xenobiotic transporters, but three specific family members have been most frequently implicated as modifiers of chemotherapy response in breast cancers [1]. These are P-glycoprotein (Pgp; encoded by the ABCB1 gene), Multidrug Resistance-associated Protein 1 (MRP1; encoded by the ABCC1 gene), and Breast Cancer Resistance Protein (BCRP; encoded by the ABCG2 gene). Given its name, relatively little is known about the expression or prognostic value of BCRP in clinical breast cancers, over-expression has been associated with drug-resistance in many in vitro studies [13], and higher expression has been associated with more advanced disease [14]
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