PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes
Manfredi Ponente, Letizia Campanini, Roberto Cuttano, Andrea Piunti, Giacomo A. Delledonne, Nadia Coltella, Roberta Valsecchi, Alessandra Villa, Ugo Cavallaro, Linda Pattini, Claudio Doglioni, Rosa Bernardi
Manfredi Ponente, Letizia Campanini, Roberto Cuttano, Andrea Piunti, Giacomo A. Delledonne, Nadia Coltella, Roberta Valsecchi, Alessandra Villa, Ugo Cavallaro, Linda Pattini, Claudio Doglioni, Rosa Bernardi
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Research Article Oncology

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

Manfredi Ponente, Letizia Campanini, Roberto Cuttano, Andrea Piunti, Giacomo A. Delledonne, Nadia Coltella, Roberta Valsecchi, Alessandra Villa, Ugo Cavallaro, Linda Pattini, Claudio Doglioni, Rosa Bernardi

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Figure 5

Arsenic trioxide inhibits migration and invasion and cooperates with chemotherapy to block metastasis in TNBC.

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Arsenic trioxide inhibits migration and invasion and cooperates with che...
(A) RT-PCR analysis of the indicated genes in the indicated cell lines untreated (NT, white dots) or treated with the indicated doses of arsenic trioxide. Data represent mean values ± SEM of 3 independent experiments. (B) Wound healing assays in the indicated cell lines treated as in A. Data are expressed as wound area reduction compared with untreated cells and represent mean values ± SEM of 3 independent experiments. (C) Invasion assays of the indicated cell lines treated as in A. Data represent the number of cells per 20× field that invaded matrigel-coated transwells. Data represent mean values ± SEM of 3 independent experiments. (D) Tumor volumes of MDA-MB-231 cells implanted in fat pads and treated with PBS (NT, white bars) or with 8 mg/Kg arsenic trioxide. Treatment was started when tumors became palpable (black arrow). Four cycles of 5 treatments followed by 2 days off treatment were performed; n = 5. (E) Number of metastatic foci per lung slides in the indicated animals; n = 5. Data represent mean values ± SEM. (F) Tumor volumes of MDA-MB-231 cells implanted in fat pads and treated with PBS (NT, white bars), 4 mg/Kg arsenic trioxide, or 20 mg/Kg paclitaxel either alone or in combination according to the schedule described in the Methods section. Treatments were started when tumors became palpable (black arrow); n = 5. (G) Number of metastatic foci per lung slides in the indicated animals; n = 5. Data represent mean values ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. Student’s 2-tailed t test was used to determine statistical significance except in panel G, where statistical analysis was performed using 1-way ANOVA (P < 0.0001) followed by Tukey’s post-hoc multiple comparison test.