Universität zu Köln

Rose, Michael, Meurer, Steffen K., Kloten, Vera, Weiskirchen, Ralf ORCID: 0000-0003-3888-0931, Denecke, Bernd, Antonopoulos, Wiebke, Deckert, Martina, Knuechel, Ruth and Dahl, Edgar (2018). ITIH5 induces a shift in TGF-beta superfamily signaling involving Endoglin and reduces risk for breast cancer metastasis and tumor death. Mol. Carcinog., 57 (2). S. 167 - 182. HOBOKEN: WILEY. ISSN 1098-2744

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Abstract

ITIH5 has been proposed being a novel tumor suppressor in various tumor entities including breast cancer. Recently, ITIH5 was furthermore identified as metastasis suppressor gene in pancreatic carcinoma. In this study we aimed to specify the impact of ITIH5 on metastasis in breast cancer. Therefore, DNA methylation of ITIH5 promoter regions was assessed in breast cancer metastases using the TCGA portal and methylation-specific PCR (MSP). We reveal that the ITIH5 upstream promoter region is particularly responsible for ITIH5 gene inactivation predicting shorter survival of patients. Notably, methylation of this upstream ITIH5 promoter region was associated with disease progression, for example, abundantly found in distant metastases. In vitro, stably ITIH5-overexpressing MDA-MB-231 breast cancer clones were used to analyze cell invasion and to identify novel ITIH5-downstream targets. Indeed, ITIH5 re-expression suppresses invasive growth of MDA-MB-231 breast cancer cells while modulating expression of genes involved in metastasis including Endoglin (ENG), an accessory TGF-beta receptor, which was furthermore co-expressed with ITIH5 in primary breast tumors. By performing in vitro stimulation of TGF-beta signaling using TGF-beta 1 and BMP-2 we show that ITIH5 triggered a TGF-beta superfamily signaling switch contributing to downregulation of targets like Id1, known to endorse metastasis. Moreover, ITIH5 predicts longer overall survival (OS) only in those breast tumors that feature high ENG expression or inversely regulated ID1 suggesting a clinical and functional impact of an ITIH5-ENG axis for breast cancer progression. Hence, we provide evidence that ITIH5 may represent a novel modulator of TGF-beta superfamily signaling involved in suppressing breast cancer metastasis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rose, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Meurer, Steffen K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kloten, Vera UNSPECIFIED UNSPECIFIED UNSPECIFIED Weiskirchen, Ralf UNSPECIFIED orcid.org/0000-0003-3888-0931 UNSPECIFIED Denecke, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Antonopoulos, Wiebke UNSPECIFIED UNSPECIFIED UNSPECIFIED Deckert, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Knuechel, Ruth UNSPECIFIED UNSPECIFIED UNSPECIFIED Dahl, Edgar UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-196609
DOI:	10.1002/mc.22742
Journal or Publication Title:	Mol. Carcinog.
Volume:	57
Number:	2
Page Range:	S. 167 - 182
Date:	2018
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1098-2744
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ALPHA-TRYPSIN INHIBITOR; CARCINOMA-IN-SITU; SUPPRESSOR GENE; HEAVY-CHAIN; EXTRACELLULAR-MATRIX; IDENTIFIES ITIH5; EXPRESSION; CELLS; INVASION; PROTEIN Multiple languages Biochemistry & Molecular Biology; Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19660