title: Expression of beclin-1 in the microenvironment of invasive ductal carcinoma of the breast: correlation with prognosis and the cancer-stromal interaction.
abstract: We examined the pathobiological properties of beclin-1, which is a key regulator of autophagosome formation in invasive ductal carcinoma of the breast, with a particular focus on the cancer microenvironment. Immunohistochemistry demonstrated that cancer cells and stromal mesenchymal cells expressed beclin-1 in 68 and 38 of 115 invasive ductal cancers, respectively. Expression of beclin-1 in cancer or stromal cells alone did not correlate with patient prognosis. In contrast, loss of beclin-1 in cancer cells and overexpression in stromal mesenchymal cells was associated with local cancer recurrence, postoperative lymph node metastasis, and a poor disease-free survival rate. A comprehensive gene expression analysis was performed on a co-culture of breast cancer cells and mesenchymal stromal cells, that latter of which either expressed beclin-1 or was depleted of beclin-1 by siRNA. Notably, siRNA-mediated downregulation of beclin-1 in mesenchymal cells co-cultured with breast cancer cells decreased the levels of various pro-inflammatory cytokines, their receptors, and collagen receptors. Quantitative reverse transcription polymerase chain reaction analysis confirmed that reduction of stromal beclin-1 expression decreased the expression of IL-1β and collagen receptor discoidin domain receptor 2 (DDR2). Microenvironmental IL-1β is believed to play an important role in tumor invasion. Recent work has also indicated that overexpression of DDR2 contributes to breast cancer invasion and lymph node metastasis. Taken together, these findings indicate beclin-1 expression in the stroma might be important for shaping the breast cancer microenvironment and thus could be a potent molecular target in patients with invasive ductal carcinoma of the breast.
authors.affiliation: Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Frontier Science for Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Morikawa
authors.affiliation: Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kito
authors.affiliation: Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Chiemi
authors.initials: C
authors.lastname: Saigo
authors.affiliation: Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Sakuratani
authors.affiliation: Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Breast and Molecular Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Futamura
authors.affiliation: Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053710:Interleukin-10 Receptor beta Subunit / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008207:Lymphatic Metastasis; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D016207:Cytokines; C081846:IL10RB protein, human; D053710:Interleukin-10 Receptor beta Subunit; D053583:Interleukin-1beta; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases