title: Loss of O⁶-methylguanine-DNA methyltransferase confers collateral sensitivity to carmustine in topoisomerase II-mediated doxorubicin resistant triple negative breast cancer cells.
abstract: Triple-negative breast cancer is characterized by aggressive tumours whose cells lack oestrogen and progesterone receptors and do not over-express HER2. It accounts for approximately 10-15% of breast cancer cases. We sought to generate a cellular model of chemotherapy drug resistance for this type of disease to provide the tools for the development of new therapies. Doxorubicin is a component of some chemotherapy regimes used to treat this form of cancer but resistance preventing disease eradication frequently occurs, mainly due to over-expression of drug transporters such as P-glycoprotein. CALDOX cells were generated by exposure of CAL51 to doxorubicin. Resistance to doxorubicin did not involve drug transporters, as the both parental and resistant cells accumulated doxorubicin to comparable levels. CALDOX cells had slower proliferation rate and an extended G1 cell cycle stage than the parental line, mainly due to an intrinsic activation of CDNK1 (p21), but this cell cycle block was not involved in the mechanism of resistance. CALDOX cells had reduced levels of TOP2A (topoisomerase IIα) and were cross resistant to the topoisomerase II inhibitors etoposide and mitoxantrone. CALDOX cells showed collateral sensitivity to carmustine due to the lack of O⁶-methylguanine-DNA-methyltransferase (MGMT) expression, related to the hypermethylation of its promoter. The collateral sensitivity of CALDOX cells to carmustine provides the rationale to evaluate MGMT promoter methylation status to design better therapeutic strategies for triple negative breast cancer.
authors.affiliation: Institute of Clinical Sciences, Imperial College London, London, UK. s.raguz@csc.mrc.ac.uk
authors.forename: Selina
authors.initials: S
authors.lastname: Raguz
authors.forename: Caroline
authors.initials: C
authors.lastname: Adams
authors.forename: Nahal
authors.initials: N
authors.lastname: Masrour
authors.forename: Sabeena
authors.initials: S
authors.lastname: Rasul
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papoutsoglou
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Giulia
authors.initials: G
authors.lastname: Cazzanelli
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Naina
authors.initials: N
authors.lastname: Patel
authors.forename: Charles
authors.initials: C
authors.lastname: Coombes
authors.forename: Ernesto
authors.initials: E
authors.lastname: Yagüe
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002330:Carmustine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011994:Recombinant Proteins; C495901:TP53 protein, human; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D019853:O(6)-Methylguanine-DNA Methyltransferase; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; D002330:Carmustine