Bcl-2 family proteins use complex intra-family interactions to regulate the intrinsic apoptotic pathway. In particular, anti-apoptotic Bcl-2 famil members (A1, Bcl-2, Bcl-xL, Bcl-w and Mcl-1) inhibit apoptosis by sequestering pro-apoptotic Bcl-2 family members (Bak, Bax, Bid, Bim and Puma). Thus, the balance of pro- to anti-apoptotic Bcl-2 proteins regulates the cellular life-death switch. In cancers, sustained overexpression of anti-apoptotic Bcl-2 family members promotes tumor cell survival. Further, anti-apoptotic Bcl-2 proteins often drive resistance of cancers to chemotherapies and targeted therapies. BH3-mimetics, small molecules designed to sequester the activity of anti-apoptotic Bcl-2 family members, were designed to combat therapeutic resistance caused by anti-apoptotic Bcl-2 proteins. In breast cancers, BH3-mimetics increase treatment-induced tumor cell killing in some but not all tumors. The mechanisms underlying resistance to these BH3-mimetics remain unclear. Our preliminary data suggest that human-derived breast cancer cell lines with MCL1 amplification display limited sensitivity to ABT-263, a BH3-mimetic targeting Bcl-2, Bcl-xL and Bcl-w, and up regulate Mcl-1 protein expression upon treatment with ABT-263. Mcl-1 knock-down increased sensitivity of breast cancer cells to ABT-263, while ectopic Mcl-1 expression enhanced ABT-263 resistance. Given the clinical impact of the Bcl-2 family in breast and other cancers, it is critical to investigate further the role of Mcl-1 in ABT-263 resistance, which we wil study in Aim 1. We further propose to study how Mcl-1 affects response of breast cancers to estrogen deprivation. Approximately 65% of breast cancers are dependent upon estrogen receptor-a (ERa) signaling, and thus are treated with ERa-targeting agents. The impact of Mcl-1 remains under-studied in this context. Our preliminary data show that Mcl-1 levels increase upon long term estrogen deprivation (LTED), a model used to mimic the estrogen-depleted conditions caused by treatment with aromatase inhibitors. We designed to combat therapeutic resistance caused by anti-apoptotic Bcl-2 proteins in Aim 2. Together, these studies will determine if Mcl-1 inhibitors, including a novel Mcl-1- specific BH3-mimetic developed by our collaborator, could be exploited clinically to improve tumor cell killing and to increase patient survival.

Public Health Relevance

Mcl-1 is an anti-apoptotic member of the Bcl-2 family of proteins, which regulate the intrinsic apoptotic pathway. We have shown that Mcl-1 loss can increase sensitivity of luminal breast cancer cells to ABT-263, a Bcl-2/Bcl-xL/Bcl-w inhibitor, and long term estrogen withdrawal, an established model of sustained treatment with aromatase inhibitors. This study will be the first to examine the role of Mcl-1 as a mediator of resistance t ABT-263 and aromatase inhibitors in luminal breast cancers, providing unprecedented knowledge and mechanistic understanding of Mcl-1 in breast cancers that could have immense clinical importance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA195989-01
Application #
8907328
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schmidt, Michael K
Project Start
2015-09-01
Project End
2018-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240
Williams, Michelle M; Lee, Linus; Werfel, Thomas et al. (2018) Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers. Cell Death Dis 9:21
Werfel, Thomas A; Wang, Shan; Jackson, Meredith A et al. (2018) Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival. Cancer Res 78:1845-1858
Williams, Michelle M; Lee, Linus; Hicks, Donna J et al. (2017) Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade. Mol Cancer Res 15:259-268
Williams, Michelle M; Vaught, David B; Joly, Meghan Morrison et al. (2017) ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation. Breast Cancer Res 19:105
Morrison Joly, Meghan; Williams, Michelle M; Hicks, Donna J et al. (2017) Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis. Breast Cancer Res 19:74
Morrison Joly, Meghan; Hicks, Donna J; Jones, Bayley et al. (2016) Rictor/mTORC2 Drives Progression and Therapeutic Resistance of HER2-Amplified Breast Cancers. Cancer Res 76:4752-64
Williams, Michelle M; Cook, Rebecca S (2015) Bcl-2 family proteins in breast development and cancer: could Mcl-1 targeting overcome therapeutic resistance? Oncotarget 6:3519-30