Chemotherapy induces Notch1-dependent MRP1 up-regulation, inhibition of which sensitizes breast cancer cells to chemotherapy.

Autor: Kim B; School of Medicine, University of Leeds, Leeds, UK. B.Kim@leeds.ac.uk.; Department of Breast Surgery, Leeds Teaching Hospitals NHS Trust, Leeds, UK. B.Kim@leeds.ac.uk., Stephen SL; School of Medicine, University of Leeds, Leeds, UK. S.L.Stephen@leeds.ac.uk., Hanby AM; School of Medicine, University of Leeds, Leeds, UK. A.M.Hanby@leeds.ac.uk.; Department of Histopathology, Leeds Teaching Hospitals NHS Trust, Leeds, UK. A.M.Hanby@leeds.ac.uk., Horgan K; Department of Breast Surgery, Leeds Teaching Hospitals NHS Trust, Leeds, UK. kieran.horgan@nhs.net., Perry SL; School of Medicine, University of Leeds, Leeds, UK. S.L.Perry@leeds.ac.uk., Richardson J; School of Medicine, University of Leeds, Leeds, UK. jewels_555@msn.com., Roundhill EA; School of Medicine, University of Leeds, Leeds, UK. E.A.Roundhill@leeds.ac.uk., Valleley EM; School of Medicine, University of Leeds, Leeds, UK. E.M.A.Valleley@leeds.ac.uk., Verghese ET; School of Medicine, University of Leeds, Leeds, UK. E.T.Verghese@leeds.ac.uk.; Department of Histopathology, Leeds Teaching Hospitals NHS Trust, Leeds, UK. E.T.Verghese@leeds.ac.uk., Williams BJ; Department of Histopathology, Leeds Teaching Hospitals NHS Trust, Leeds, UK. bethwilliams35@hotmail.com., Thorne JL; School of Food Science and Nutrition, University of Leeds, Leeds, UK. J.L.Thorne@leeds.ac.uk., Hughes TA; School of Medicine, University of Leeds, Leeds, UK. t.hughes@leeds.ac.uk.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2015 Sep 11; Vol. 15, pp. 634. Date of Electronic Publication: 2015 Sep 11.
DOI: 10.1186/s12885-015-1625-y
Abstrakt: Background: Multi-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.
Methods: MRP1 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.
Results: In 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.
Conclusions: Notch inhibitors may have potential in sensitizing breast cancer cells to chemotherapeutics and therefore in tackling chemoresistance.
Databáze: MEDLINE
Externí odkaz: