APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer.

Abstract

APRIL (a proliferation-inducing ligand) is a cytokine of the tumor necrosis factor family associated mainly with hematologic malignancies. APRIL is also overexpressed in breast carcinoma tissue lesions, although neither its role in breast tumorigenesis nor the underlying molecular mechanism is known. Here, we show that several breast cancer cell lines express APRIL and both its receptors, B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), independently of luminal or basal tumor cell phenotype, and that the mitogen-activated protein kinases p38, ERK1/2, and JNK1/2 are activated in response to APRIL. The inflammatory stimulus poly I:C, a toll-like receptor (TLR) 3 ligand, enhanced APRIL secretion. Silencing experiments decreased cell proliferation, demonstrating that APRIL is a critical autocrine factor for breast tumor growth. Studies of 4T1 orthotopic breast tumors in APRIL transgenic mice showed that an APRIL-enriched environment increased tumor growth and promoted lung metastasis associated with enhanced tumor cell proliferation; BCMA and TACI expression suggests that both participate in these processes. We detected APRIL, BCMA and TACI in human luminal, triple-negative breast carcinomas and HER2 breast carcinomas, with increased levels in more aggressive basal tumors. APRIL was observed near Ki67(+) nuclei and was distributed heterogeneously in the cancer cells, in the leukocyte infiltrate, and in the myoepithelial layer adjacent to the tumor area; these results imply that APRIL provides proliferation signals to tumor cells through paracrine and autocrine signaling. Our study identifies participation of APRIL signaling in breast cancer promotion; we propose impairment of this pathway as a potential therapeutic strategy.

• Authors: Araceli García-Castro, Manuela Zonca, Douglas Florindo-Pinheiro, Carla E Carvalho-Pinto, Alex Cordero, Burgo Gutiérrez del Fernando, Aránzazu García-Grande, Santos Mañes, Michael Hahne, Eva González-Suárez, Lourdes Planelles
• Journal: Carcinogenesis (Carcinogenesis) Vol. 36 Issue 5 Pg. 574-84 (May 2015) ISSN: 1460-2180 [Electronic] England
• PMID: 25750171 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• B-Cell Maturation Antigen
• Biomarkers, Tumor
• RNA, Messenger
• TNFRSF13B protein, human
• TNFRSF17 protein, human
• TNFSF13 protein, human
• Transmembrane Activator and CAML Interactor Protein
• Tumor Necrosis Factor Ligand Superfamily Member 13

Topics

• Animals
• Apoptosis
• B-Cell Maturation Antigen (genetics, metabolism)
• Biomarkers, Tumor (genetics, metabolism)
• Blotting, Western
• Breast Neoplasms (genetics, metabolism, pathology)
• Carcinoma, Basal Cell (genetics, metabolism, pathology)
• Cell Proliferation
• Female
• Fluorescent Antibody Technique
• Humans
• Immunoenzyme Techniques
• Lung Neoplasms (genetics, metabolism, secondary)
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Transmembrane Activator and CAML Interactor Protein (genetics, metabolism)
• Tumor Cells, Cultured
• Tumor Necrosis Factor Ligand Superfamily Member 13 (genetics, metabolism)
• Xenograft Model Antitumor Assays