title: Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance.
abstract: Stem cell antigen Sca-1 is implicated in murine cancer stem cell biology and breast cancer models, but the role of its human homologs Ly6K and Ly6E in breast cancer are not established. Here we report increased expression of Ly6K/E in human breast cancer specimens correlates with poor overall survival, with an additional specific role for Ly6E in poor therapeutic outcomes. Increased expression of Ly6K/E also correlated with increased expression of the immune checkpoint molecules PDL1 and CTLA4, increased tumor-infiltrating T regulatory cells, and decreased natural killer (NK) cell activation. Mechanistically, Ly6K/E was required for TGFβ signaling and proliferation in breast cancer cells, where they contributed to phosphorylation of Smad1/5 and Smad2/3. Furthermore, Ly6K/E promoted cytokine-induced PDL1 expression and activation and binding of NK cells to cancer cells. Finally, we found that Ly6K/E promoted drug resistance and facilitated immune escape in this setting. Overall, our results establish a pivotal role for a Ly6K/E signaling axis involving TGFβ in breast cancer pathophysiology and drug response, and highlight this signaling axis as a compelling realm for therapeutic invention. Cancer Res; 76(11); 3376-86. ©2016 AACR.
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC.
authors.forename: Midrar
authors.initials: M
authors.lastname: AlHossiny
authors.affiliation: Innovation Center for Biomedical Informatics (ICBI), Georgetown University Medical Center, Washington, DC.
authors.forename: Linlin
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC.
authors.forename: William R
authors.initials: WR
authors.lastname: Frazier
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC.
authors.forename: Noriko
authors.initials: N
authors.lastname: Steiner
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC. Innovation Center for Biomedical Informatics (ICBI), Georgetown University Medical Center, Washington, DC.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Gusev
authors.affiliation: Department of Pathology, Georgetown University Medical Center, Washington, DC.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kallakury
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC.
authors.forename: Eric
authors.initials: E
authors.lastname: Glasgow
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC.
authors.forename: Karen
authors.initials: K
authors.lastname: Creswell
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC. Innovation Center for Biomedical Informatics (ICBI), Georgetown University Medical Center, Washington, DC.
authors.forename: Subha
authors.initials: S
authors.lastname: Madhavan
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC. Innovation Center for Biomedical Informatics (ICBI), Georgetown University Medical Center, Washington, DC. geeta.upadhyay@georgetown.edu.
authors.forename: Geeta
authors.initials: G
authors.lastname: Upadhyay
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism*; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000950:Antigens, Ly; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; C439870:LY6E protein, human; C525725:LY6K protein, human; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta