title: Interleukin-30 Promotes Breast Cancer Growth and Progression.
abstract: The inflammatory tissue microenvironment that promotes the development of breast cancer is not fully understood. Here we report a role for elevated IL30 in supporting the breast cancer cell viability and invasive migration. IL30 was absent in normal mammary ducts, ductules, and acini of histologically normal breast and scanty in the few stromal infiltrating leukocytes. In contrast, IL30 was expressed frequently in breast cancer specimens where it was associated with triple-negative and HER2+molecular subtypes. In stromal leukocytes found in primary tumors or tumor-draining lymph nodes, which included mainly CD14+monocytes, CD68+macrophages, and CD33+/CD11b+myeloid cells, IL30 levels increased with disease stage and correlated with recurrence. A negative correlation was determined between IL30 expression by nodal stromal leukocytes and overall survival. In vitro studies showed that human recombinant IL30 upregulated expression of a pro-oncogenic program, including especially IL6 in both triple-negative and HER2+breast cancer cells. In triple-negative breast cancer cells, IL30 boosted a broader program of proliferation, invasive migration, and an inflammatory milieu associated with KISS1-dependent metastasis. Silencing of STAT1/STAT3 signaling hindered the regulation of the primary growth and progression factors in breast cancer cells. IL30 administration in vivo fostered the growth of triple-negative breast cancer by promoting proliferation and vascular dissemination of cancer cells and the accumulation of intratumoral CD11b+/Gr1+myeloid cell infiltrates. Overall, our results show how IL30 regulates breast cancer cell viability, migration, and gene expression to promote breast cancer growth and progression and its impact on patient outcome. Cancer Res; 76(21); 6218-29. ©2016 AACR.
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Irma
authors.initials: I
authors.lastname: Airoldi
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cocco
authors.affiliation: Department of Medicine and Sciences of Aging, Division of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I.-MeT, Aging Research Center, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sorrentino
authors.affiliation: Division of Pathology, "SS. Annunziata Hospital", Chieti, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Angelucci
authors.affiliation: Department of Medicine and Sciences of Aging, Division of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I.-MeT, Aging Research Center, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Di Meo
authors.affiliation: Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Lamberto
authors.initials: L
authors.lastname: Manzoli
authors.affiliation: Department of Medicine and Sciences of Aging, Division of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy.|Ce.S.I.-MeT, Aging Research Center, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Esposito
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, and National Cancer Institute "Giovanni Paolo II", Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.affiliation: Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Bertolotto
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Iezzi
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Natoli
authors.affiliation: Department of Medicine and Sciences of Aging, Division of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy. edicarlo@unich.it.|Ce.S.I.-MeT, Aging Research Center, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Di Carlo
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D006801:Humans; D007378:Interleukins / Q000032:analysis / Q000502:physiology*; D051379:Mice; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D050794:STAT1 Transcription Factor / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D064726:Triple Negative Breast Neoplasms / Q000473:pathology
chemical_list: D007378:Interleukins; D018719:Erb-b2 Receptor Tyrosine Kinases; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C464565:MYDGF protein, human; C508053:ERBB2 protein, human