Abstract
BackgroundMulti-drug Resistance associated Protein-1 (MRP1) can export chemotherapeutics from cancer cells and is implicated in chemoresistance, particularly as is it known to be up-regulated by chemotherapeutics. Our aims in this study were to determine whether activation of Notch signalling is responsible for chemotherapy-induced MRP1 expression Notch in breast cancers, and whether this pathway can be manipulated with an inhibitor of Notch activity.MethodsMRP1 and Notch1 were investigated in 29 patients treated with neoadjuvant chemotherapy (NAC) for breast cancer, using immunohistochemistry on matched biopsy (pre-NAC) and surgical samples (post-NAC). Breast epithelial cell cultures (T47D, HB2) were treated with doxorubicin in the presence and absence of functional Notch1, and qPCR, siRNA, Western blots, ELISAs and flow-cytometry were used to establish interactions.ResultsIn clinical samples, Notch1 was activated by neoadjuvant chemotherapy (Wilcoxon signed-rank p < 0.0001) and this correlated with induction of MRP1 expression (rho = 0.6 p = 0.0008). In breast cell lines, doxorubicin induced MRP1 expression and function (non-linear regression p < 0.004). In the breast cancer line T47D, doxorubicin activated Notch1 and, critically, inhibition of Notch1 activation with the γ-secretase inhibitor DAPT abolished the doxorubicin-induced increase in MRP1 expression and function (t-test p < 0.05), resulting in enhanced cellular retention of doxorubicin and increased doxorubicin-induced apoptosis (t-test p = 0.0002). In HB2 cells, an immortal but non-cancer derived breast cell line, Notch1-independent MRP1 induction was noted and DAPT did not enhance doxorubicin-induced apoptosis.ConclusionsNotch inhibitors may have potential in sensitizing breast cancer cells to chemotherapeutics and therefore in tackling chemoresistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1625-y) contains supplementary material, which is available to authorized users.
Highlights
Multi-drug Resistance associated Protein-1 (MRP1) can export chemotherapeutics from cancer cells and is implicated in chemoresistance, as is it known to be up-regulated by chemotherapeutics
MRP1 and Notch1IC are up-regulated in breast cancers by chemotherapy In order to assess the relevance of MRP1 expression and Notch signalling in chemotherapy treatment, the expression levels of MRP1 and activated Notch1, Notch1IC, were examined using immunohistochemistry in tumours from 29 breast patients treated with neoadjuvant chemotherapy (NAC)
We concluded that our data were compatible with Notch1 signalling playing a role in chemotherapy-induced upregulation of MRP1 expression
Summary
Multi-drug Resistance associated Protein-1 (MRP1) can export chemotherapeutics from cancer cells and is implicated in chemoresistance, as is it known to be up-regulated by chemotherapeutics. Elucidation and targeting of tumour specific pathways that regulate expression of ABCs may present methods to inhibit ABC function in cancer cells, thereby sensitizing them to chemotherapy agents, while reducing side effects associated with unwanted influences in normal cells. MRP1 was shown to be a direct transcriptional target of Notch in the multi-drug resistant breast cancer cell line, MCF7-VP [12]. Notch signalling was shown to be significantly up-regulated in breast tumours of patients treated with neoadjuvant chemotherapy (NAC) [13]. Based on these observations, our hypothesis was that in some breast cancers chemotherapy drives MRP1-dependent acquired resistance via Notch signalling
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
