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.
Highlights
Triple-negative breast cancer (TNBC) consists of a diverse and heterogeneous group of tumors that by definition lack estrogen and progesterone receptors and amplification of the HER2 gene [1]
Expression of Hypermethylated in cancer 1 (HIC1) is silenced in TNBC Increasing evidence indicates that HIC1 is silenced by epigenetic modifications in many types of prevalent human tumors [11,12,13,14, 24]
LCN2 was markedly amplified from the HIC1-immunoprecipitated BT474 and MCF-7 chromatins, but absent from chromatin immunoprecipitated by the control rabbit immunoglobulin G. These results demonstrate that endogenous HIC1 proteins can be directly recruited onto the LCN2 promoter to repress its expression, whereas the silenced HIC1 expression in TNBC cells may facilitate the escape of LCN2 from the suppressive modulation
Summary
Triple-negative breast cancer (TNBC) consists of a diverse and heterogeneous group of tumors that by definition lack estrogen and progesterone receptors and amplification of the HER2 gene [1]. Recent studies showed that HIC1 promoter hypermethylation is present in solid tumors and in normal breast ductal [6], brain [7], and prostate epithelium tissues [3]. These findings indicate that other inhibitory mechanisms besides hypermethylation may exist, such as the modification of HIC1 by Authors' Affiliations: 1Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine; and 2Comprehensive Breast Health Center, Rui Jin Hospital, Shanghai, China
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