title: HIC1 silencing in triple-negative breast cancer drives progression through misregulation of LCN2.
abstract: The tumor suppressor gene HIC1 is frequently deleted or epigenetically silenced in human cancer, where its restoration may improve cancer prognosis. Here, we report results illuminating how HIC1 silencing alters effect or signals in triple-negative breast cancer (TNBC), which are crucial for its pathogenesis. HIC1 expression was silenced only in TNBC compared with other molecular subtypes of breast cancer. Restoring HIC1 expression in TNBC cells reduced cell migration, invasion, and metastasis, whereas RNAi-mediated silencing of HIC1 in untransformed human breast cells increased their invasive capabilities. Mechanistic investigations identified the small-secreted protein lipocalin-2 (LCN2), as a critical downstream target of HIC1 in TNBC cells. Elevating LCN2 expression in cells expressing HIC1 partially rescued its suppression of cell invasion and metastasis. Notably, autocrine secretion of LCN2 induced by loss of HIC1 activated the AKT pathway through the neutrophil gelatinase-associated lipocalin receptor, which is associated with TNBC progression. Taken together, our findings revealed that the HIC1-LCN2 axis may serve as a subtype-specific prognostic biomarker, providing an appealing candidate target for TNBC therapy.
authors.affiliation: Authors' Affiliations: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine; and Comprehensive Breast Health Center, Rui Jin Hospital, Shanghai, China.
authors.forename: Guangcun
authors.initials: G
authors.lastname: Cheng
authors.forename: Xueqing
authors.initials: X
authors.lastname: Sun
authors.forename: Jinglong
authors.initials: J
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Xiao
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wang
authors.forename: Xuemei
authors.initials: X
authors.lastname: Fan
authors.forename: Lidong
authors.initials: L
authors.lastname: Zu
authors.forename: Mingang
authors.initials: M
authors.lastname: Hao
authors.forename: Qing
authors.initials: Q
authors.lastname: Qu
authors.forename: Yan
authors.initials: Y
authors.lastname: Mao
authors.forename: Yunjing
authors.initials: Y
authors.lastname: Xue
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D064593:Heterografts; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics*; D051379:Mice; D010641:Phenotype; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality
chemical_list: D000209:Acute-Phase Proteins; C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt