Triple negative breast cancer (TNBC) represents an aggressive subtype for which only chemotherapy is available. The RB1 tumour suppressor is frequently lost in human breast cancer, primarily in TNBC. Loss of RB1 deregulates the cell cycle and is thought to affect BC response to endocrine, radiation, and chemotherapy. However, the global chemosensitivity of Rb null BC is not known. Here I demonstrate that RB1-deficient TNBC cells are highly sensitive to radiation, and moderately sensitive to doxorubicin and methotrexate. However, loss of RB1 does not increase sensitivity to multiple other drugs. Moreover, a non-biased screen of 2 RB-deficient versus 2 RB-proficient lines with ~3500 drugs did not reveal any difference in sensitivity, but identified disulfiram as a potent drug, which compared favourably with current chemotherapeutics against TNBC. Disulfiram’s efficacy was validated against 13 human TNBC
lines with an average IC50 of 300nM. IQGAP1 was identified as a potential target of disulfiram.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/65435 |
| Date | 18 June 2014 |
| Creators | Robinson, Tyler |
| Contributors | Zacksenhaus, Eldad |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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