APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer.
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.
Immunology and Oncology Department, Centro Nacional de Biotecnología/CSIC, UAM Cantoblanco, Madrid, Spain.
Araceli
A
García-Castro
Immunology and Oncology Department, Centro Nacional de Biotecnología/CSIC, UAM Cantoblanco, Madrid, Spain.
Manuela
M
Zonca
Immunology and Oncology Department, Centro Nacional de Biotecnología/CSIC, UAM Cantoblanco, Madrid, Spain.
Douglas
D
Florindo-Pinheiro
Immunology and Oncology Department, Centro Nacional de Biotecnología/CSIC, UAM Cantoblanco, Madrid, Spain, Immunobiology Department, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil.
Carla E
CE
Carvalho-Pinto
Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain.
Alex
A
Cordero
Immunology and Oncology Department, Centro Nacional de Biotecnología/CSIC, UAM Cantoblanco, Madrid, Spain.
Burgo
B
Gutiérrez del Fernando
Flow Cytometry Core Facility, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain and.
Aránzazu
A
García-Grande
Immunology and Oncology Department, Centro Nacional de Biotecnología/CSIC, UAM Cantoblanco, Madrid, Spain.
Santos
S
Mañes
Institute de Génétique Moléculaire de Montpellier, Montpellier, France.
Michael
M
Hahne
Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain.
Eva
E
González-Suárez
Immunology and Oncology Department, Centro Nacional de Biotecnología/CSIC, UAM Cantoblanco, Madrid, Spain, lplanelles@cnb.csic.es.
Lourdes
L
Planelles
D000818:Animals; D017209:Apoptosis; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D053301:B-Cell Maturation Antigen; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C108467:TNFRSF13B protein, human; C086966:TNFRSF17 protein, human; C114631:TNFSF13 protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13