title: PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes.
abstract: Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometastatic function in TNBC that can be targeted by arsenic trioxide. We found that, in TNBC patients, constitutive HIF1A activity induces high expression of PML, along with a number of HIF1A target genes that promote metastasis at multiple levels. Intriguingly, PML controls the expression of these genes by binding to their regulatory regions along with HIF1A. This mechanism is specific to TNBC cells and does not occur in other subtypes of breast cancer where PML and prometastatic HIF1A target genes are underexpressed. As a consequence, PML promotes cell migration, invasion, and metastasis in TNBC cell and mouse models. Notably, pharmacological inhibition of PML with arsenic trioxide, a PML-degrading agent used to treat promyelocytic leukemia patients, delays tumor growth, impairs TNBC metastasis, and cooperates with chemotherapy by preventing metastatic dissemination. In conclusion, we report identification of a prometastatic pathway in TNBC and suggest clinical development toward the use of arsenic trioxide for TNBC patients.
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute.|Vita-Salute San Raffaele University.
authors.forename: Manfredi
authors.initials: M
authors.lastname: Ponente
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute.|Vita-Salute San Raffaele University.
authors.forename: Letizia
authors.initials: L
authors.lastname: Campanini
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cuttano
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute.
authors.forename: Andrea
authors.initials: A
authors.lastname: Piunti
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute.
authors.forename: Giacomo A
authors.initials: GA
authors.lastname: Delledonne
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute.
authors.forename: Nadia
authors.initials: N
authors.lastname: Coltella
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute.
authors.forename: Roberta
authors.initials: R
authors.lastname: Valsecchi
authors.affiliation: Department of Experimental Oncology and Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Villa
authors.affiliation: Department of Experimental Oncology and Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Cavallaro
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Pattini
authors.affiliation: Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bernardi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071156:Promyelocytic Leukemia Protein; C070576:PML protein, human