Evasion of cell death is essential to every step of tumorigenesis. Anti-apoptotic Bcl-2 family proteins are master inhibitors of cell death, and thus are often overexpressed in cancers. In particular, Bcl-2, Bcl-xL, and Mcl-1 are highly expressed in Estrogen Receptor-alpha positive (ERα+) breast cancers. However, one anti-apoptotic Bcl-2 family protein, Mcl-1, is understudied in ERα+ breast cancers. Herein we show that Mcl-1 is essential to ERα+ breast tumor cell survival, and is a more potent tumor cell survival factor than other family members, like Bcl-2 and Bcl-xL. Interestingly, Mcl-1 expression and activity increased upon Bcl-2/Bcl-xL dual inhibition with ABT-263, mediated by increased Mcl-1 cap-dependent translation. Blockade of cap-dependent translation, through inhibition of mTORC1 signaling, resulted in tumor cell killing in cell culture and in vivo, phenocopying ablation of Mcl-1 by RNA-interference. Mcl-1 depletion in combination with ABT-263 restored sensitivity to Bcl-2/Bcl-xL blockade, suggesting that Mcl-1 is a primary resistance factor to Bcl-2/Bcl-xL inhibition in ERα+ breast cancers. Importantly, preliminary studies suggest that anti-apoptotic Bcl-2 family proteins can promote resistance to standard of care breast cancer therapies. Mcl-1 inhibition, but not Bcl-2/Bcl-xL blockade, promoted cell death in a model of anti-estrogen resistance, long term estrogen deprivation (LTED). Mcl-1 inhibition using polymeric nanoparticles containing Mcl-1 siRNA (si-NPs), increased tumor cell death in combination with LTED and after treatment with the selective estrogen receptor downregulator fulvestrant. Therefore, Mcl-1 is a dominant tumor cell survival factor in ERα+ breast cancers that is rapidly and potently upregulated in response to targeted therapies. However, dependence on Mcl-1 for tumor cell survival may be clinically thwarted using mTOR inhibitors or si-NPs.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07182017-085645 |
| Date | 31 July 2017 |
| Creators | Williams, Michelle Marie |
| Contributors | Rebecca S. Cook, Jin Chen, Thomas Stricker, Sandra Zinkel |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-07182017-085645/ |
| Rights | restrictone, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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