Both bulk and cancer stem cell subpopulations in triple-negative breast cancer are susceptible to Wnt, HDAC, and ERα coinhibition

Andrew Sulaiman; Brandon Sulaiman; Lara Khouri; Sarah McGarry; Carolyn Nessim; Angel Arnaout; Xuguang Li; Christina Addison; Jim Dimitroulakos; Lisheng Wang

doi:10.1002/1873-3468.12496

Both bulk and cancer stem cell subpopulations in triple-negative breast cancer are susceptible to Wnt, HDAC, and ERα coinhibition

FEBS Lett. 2016 Dec;590(24):4606-4616. doi: 10.1002/1873-3468.12496. Epub 2016 Dec 9.

Authors

Andrew Sulaiman¹, Brandon Sulaiman¹, Lara Khouri¹, Sarah McGarry¹, Carolyn Nessim², Angel Arnaout², Xuguang Li^{1

3}, Christina Addison^{1

2}, Jim Dimitroulakos^{1

2}, Lisheng Wang^{1

4

5}

Affiliations

¹ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.
² Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Canada.
³ Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada Sir Frederick G. Banting Research Centre, Ottawa, Canada.
⁴ Regenerative Medicine Program, Ottawa Hospital Research Institute, Canada.
⁵ Ottawa Institute of Systems Biology, University of Ottawa, Canada.

PMID: 27859250
DOI: 10.1002/1873-3468.12496

Abstract

Development of targeted therapies for triple-negative breast cancer (TNBC, a more aggressive subtype) is an unmet medical need. We analyzed data from 887 patients with invasive breast cancer and observed that increased Wnt and histone deacetylase (HDAC) activities are associated with estrogen receptor 1 (ESR1) and progesterone receptor (PGR) repression, poor survival, and increased relapse. The inverse correlation between Wnt signaling and repression of ESR1 and PGR expression was found to be magnified in cancer stem cell (CSC) subpopulations in TNBC cell lines. Cosuppression of Wnt, HDAC, and ESR1 using clinically relevant low-dose inhibitors effectively repressed both bulk and CSC subpopulations and converted CSCs to non-CSCs in TNBC cells without affecting MCF-10A mammary epithelial cells.

Keywords: HDAC; TNBC; ESR1; Wnt; cancer stem cell.

Publication types

Letter

MeSH terms

Antineoplastic Agents / pharmacology*
CD24 Antigen / genetics
CD24 Antigen / metabolism
Cell Line
Cell Proliferation / drug effects
Epithelial Cells / cytology
Epithelial Cells / drug effects
Epithelial Cells / metabolism
Estrogen Receptor alpha / antagonists & inhibitors*
Estrogen Receptor alpha / genetics
Estrogen Receptor alpha / metabolism
Female
Gene Expression Regulation, Neoplastic*
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylases / genetics*
Histone Deacetylases / metabolism
Humans
Hyaluronan Receptors / genetics
Hyaluronan Receptors / metabolism
Neoplastic Stem Cells / drug effects*
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Receptor, ErbB-2 / deficiency
Receptor, ErbB-2 / genetics
Receptors, Progesterone / deficiency
Receptors, Progesterone / genetics
Signal Transduction
Survival Analysis
Tamoxifen / pharmacology
Triple Negative Breast Neoplasms / genetics*
Triple Negative Breast Neoplasms / metabolism
Triple Negative Breast Neoplasms / mortality
Triple Negative Breast Neoplasms / pathology
Valproic Acid / pharmacology
Wnt Proteins / antagonists & inhibitors*
Wnt Proteins / genetics
Wnt Proteins / metabolism
beta Catenin / antagonists & inhibitors
beta Catenin / genetics
beta Catenin / metabolism

Substances

Antineoplastic Agents
CD24 Antigen
CD24 protein, human
CD44 protein, human
CTNNB1 protein, human
ESR1 protein, human
Estrogen Receptor alpha
Histone Deacetylase Inhibitors
Hyaluronan Receptors
RNA, Small Interfering
Receptors, Progesterone
Wnt Proteins
beta Catenin
Tamoxifen
Valproic Acid
ERBB2 protein, human
Receptor, ErbB-2
Histone Deacetylases