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Title page for ETD etd-07182017-085645


Type of Document Dissertation
Author Williams, Michelle Marie
Author's Email Address mwilli323@gmail.com
URN etd-07182017-085645
Title Mcl-1 Drives Resistance of Estrogen Receptor-α Positive Breast Cancers to Targeted Therapies
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Jin Chen Committee Chair
Rebecca S. Cook Committee Member
Sandra Zinkel Committee Member
Thomas Stricker Committee Member
Keywords
  • Mcl-1
  • therapeutic resistance
  • Bcl-2 family proteins
  • luminal breast cancers
Date of Defense 2017-06-22
Availability restrictone
Abstract
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.
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