Deptor enhances triple-negative breast cancer metastasis and chemoresistance through coupling to survivin expression

Jenny G Parvani; Gangarao Davuluri; Michael K Wendt; Christine Espinosa; Maozhen Tian; David Danielpour; Khalid Sossey-Alaoui; William P Schiemann

doi:10.1016/j.neo.2015.02.003

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Deptor enhances triple-negative breast cancer metastasis and chemoresistance through coupling to survivin expression

Journal article

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Deptor enhances triple-negative breast cancer metastasis and chemoresistance through coupling to survivin expression

Jenny G Parvani, Gangarao Davuluri, Michael K Wendt, Christine Espinosa, Maozhen Tian, David Danielpour, Khalid Sossey-Alaoui and William P Schiemann

Neoplasia (New York, N.Y.), Vol.17(3), pp.317-328

03/01/2015

DOI: 10.1016/j.neo.2015.02.003

PMCID: 4372649

PMID: 25810016

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Abstract

Transforming growth factor-β (TGF-β) functions to suppress tumorigenesis in normal mammary tissues and early-stage breast cancers and, paradoxically, acts to promote the metastasis and chemoresistance in late-stage breast cancers, particularly triple-negative breast cancers (TNBCs). Precisely how TGF-β acquires oncogenic characteristics in late-stage breast cancers remains unknown, as does the role of the endogenous mammalian target of rapamycin (mTOR) inhibitor, Dep domain-containing mTOR-interacting protein (Deptor), in coupling TGF-β to TNBC development and metastatic progression. Here we demonstrate that Deptor expression was downregulated in basal-like/TNBCs relative to their luminal counterparts. Additionally, Deptor expression was 1) inversely correlated with the metastatic ability of human (MCF10A) and mouse (4T1) TNBC progression series and 2) robustly repressed by several inducers of epithelial-mesenchymal transition programs. Functional disruption of Deptor expression in 4T07 cells significantly inhibited their proliferation and organoid growth in vitro, as well as prevented their colonization and tumor formation in the lungs of mice. In stark contrast, elevated Deptor expression was significantly associated with poorer overall survival of patients harboring estrogen receptor α-negative breast cancers. Accordingly, enforced Deptor expression in MDA-MB-231 cells dramatically enhanced their 1) organoid growth in vitro, 2) pulmonary outgrowth in mice, and 3) resistance to chemotherapies, an event dependent on the coupling of Deptor to survivin expression. Collectively, our findings highlight the dichotomous functions of Deptor in modulating the proliferation and survival of TNBCs during metastasis; they also implicate Deptor and its stimulation of survivin as essential components of TNBC resistance to chemotherapies and apoptotic stimuli.

Animals

Caspases - metabolism

Cell Line, Tumor

Cell Survival - genetics

Disease Models, Animal

Drug Resistance, Neoplasm - genetics

Epithelial-Mesenchymal Transition - genetics

Estrogen Receptor alpha - metabolism

Female

Gene Expression Regulation, Neoplastic - drug effects

Heterografts

Humans

Inhibitor of Apoptosis Proteins - genetics

Intracellular Signaling Peptides and Proteins - deficiency

Intracellular Signaling Peptides and Proteins - genetics

Intracellular Signaling Peptides and Proteins - metabolism

Mice

Neoplasm Metastasis

Signal Transduction - drug effects

Smad3 Protein - metabolism

Transforming Growth Factor beta - metabolism

Transforming Growth Factor beta - pharmacology

Triple Negative Breast Neoplasms - genetics

Triple Negative Breast Neoplasms - metabolism

Triple Negative Breast Neoplasms - pathology

Details

Title: Subtitle: Deptor enhances triple-negative breast cancer metastasis and chemoresistance through coupling to survivin expression
Creators: Jenny G Parvani - Case Western Reserve University
Gangarao Davuluri - Cleveland Clinic Lerner College of Medicine
Michael K Wendt - Purdue University West Lafayette
Christine Espinosa - Case Western Reserve University
Maozhen Tian - Case Western Reserve University
David Danielpour - Case Western Reserve University
Khalid Sossey-Alaoui - Cleveland Clinic Lerner College of Medicine
William P Schiemann - Case Western Reserve University
Resource Type: Journal article
Publication Details: Neoplasia (New York, N.Y.), Vol.17(3), pp.317-328
DOI: 10.1016/j.neo.2015.02.003
PMID: 25810016
PMCID: 4372649
NLM abbreviation: Neoplasia
ISSN: 1476-5586
eISSN: 1476-5586
Grant note: CA177069 / NCI NIH HHS R01 CA177069 / NCI NIH HHS R01 CA129359 / NCI NIH HHS CA129359 / NCI NIH HHS
Language: English
Date published: 03/01/2015
Academic Unit: Internal Medicine
Record Identifier: 9984459619502771

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