title: CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer.
abstract: Using gene-expression data from over 6,000 breast cancer patients, we report herein that high CD73 expression is associated with a poor prognosis in triple-negative breast cancers (TNBC). Because anthracycline-based chemotherapy regimens are standard treatment for TNBC, we investigated the relationship between CD73 and anthracycline efficacy. In TNBC patients treated with anthracycline-only preoperative chemotherapy, high CD73 gene expression was significantly associated with a lower rate of pathological complete response or the disappearance of invasive tumor at surgery. Using mouse models of breast cancer, we demonstrated that CD73 overexpression in tumor cells conferred chemoresistance to doxorubicin, a commonly used anthracycline, by suppressing adaptive antitumor immune responses via activation of A2A adenosine receptors. Targeted blockade of CD73 enhanced doxorubicin-mediated antitumor immune responses and significantly prolonged the survival of mice with established metastatic breast cancer. Taken together, our data suggest that CD73 constitutes a therapeutic target in TNBC.
authors.affiliation: Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.forename: Sandra
authors.initials: S
authors.lastname: Pommey
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: Paul A
authors.initials: PA
authors.lastname: Beavis
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: John
authors.initials: J
authors.lastname: Stagg
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D018943:Anthracyclines / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000276:immunology; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D011379:Prognosis
chemical_list: D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D004317:Doxorubicin; D015720:5'-Nucleotidase; C548241:NT5E protein, human
keywords: ectonucleotidase; immunogenic cell death; immunotherapy