title: Deptor enhances triple-negative breast cancer metastasis and chemoresistance through coupling to survivin expression.
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.
authors: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors: Jenny G
authors: JG
authors: Parvani
authors: Department of Molecular Cardiology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
authors: Gangarao
authors: G
authors: Davuluri
authors: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
authors: Michael K
authors: MK
authors: Wendt
authors: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors: Christine
authors: C
authors: Espinosa
authors: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors: Maozhen
authors: M
authors: Tian
authors: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors: David
authors: D
authors: Danielpour
authors: Department of Molecular Cardiology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
authors: Khalid
authors: K
authors: Sossey-Alaoui
authors: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA. Electronic address: wps20@case.edu.
authors: William P
authors: WP
authors: Schiemann
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D000077022:Survivin; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: C107489:BIRC5 protein, human; D047628:Estrogen Receptor alpha; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051900:Smad3 Protein; D000077022:Survivin; D016212:Transforming Growth Factor beta; C556139:DEPTOR protein, human; D020169:Caspases