Chemotherapy induces Notch1-dependent MRP1 up-regulation, inhibition of which sensitizes breast cancer cells to chemotherapyReportar como inadecuado




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BMC Cancer

, 15:634

First Online: 11 September 2015Received: 08 April 2015Accepted: 24 August 2015DOI: 10.1186-s12885-015-1625-y

Cite this article as: Kim, B., Stephen, S.L., Hanby, A.M. et al. BMC Cancer 2015 15: 634. doi:10.1186-s12885-015-1625-y

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.

AbbreviationsABCATP-binding cassette

DAPTN-N-3,5-Difluorophenacetyl-L-alanyl-S-phenylglycine t-butyl ester

ELISAEnzyme-Linked ImmunoSorbent Assay

MRP1Multi-drug Resistance associated Protein-1

NACneoadjuvant chemotherapy

Notch1Notch1 intracellular domain

PIpropidium iodine

qPCRquantitative polymerase chain reaction

Electronic supplementary materialThe online version of this article doi:10.1186-s12885-015-1625-y contains supplementary material, which is available to authorized users.

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Autor: Baek Kim - Sam L. Stephen - Andrew M. Hanby - Kieran Horgan - Sarah L. Perry - Julie Richardson - Elizabeth A. Roundhil

Fuente: https://link.springer.com/







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