Universität zu Köln

Heilmann, Thorsten, Vondung, Florian, Borzikowsky, Christoph ORCID: 0000-0002-5489-0032, Szymczak, Silke ORCID: 0000-0002-8897-9035, Krueger, Sandra, Alkatout, Ibrahim, Wenners, Antonia, Bauer, Maret, Klapper, Wolfram, Roecken, Christoph, Maass, Nicolai, von Karstedt, Silvia, Schem, Christian and Trauzold, Anna (2019). Heterogeneous intracellular TRAIL-receptor distribution predicts poor outcome in breast cancer patients. J. Mol. Med., 97 (8). S. 1155 - 1168. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-1440

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Abstract

Upon ligand binding, plasma membrane-located TNF-related apoptosis-inducing ligand (TRAIL)-receptors 1 and 2 induce apoptosis as well as cancer-promoting signaling in cancer cells. TRAIL-R3 and TRAIL-R4 are believed to negatively regulate TRAIL-mediated apoptosis. Intracellular localization of TRAIL-receptors, as observed in many tumor cells, has been associated with oncogenic features, which are distinct from membrane-associated TRAIL-R signaling. Here, analyzing a panel of 354 breast cancer specimens, we found that an unfavorable outcome correlating with cancer-promoting properties of TRAIL-R1, TRAIL-R2, and TRAIL-R4 was most significantly defined by their intracellular distribution and mutual co-expression. A nuclear or cytoplasmic heterogeneous expression pattern correlated with markedly decreased overall survival and discriminated high-risk breast cancer patients from low-risk patients with a homogeneous distribution of expression, i.e., nuclear and cytoplasmic expression. The homogeneous TRAIL-R expression was associated with favorable breast cancer surrogate markers corresponding with excellent survival prognoses at 5years after diagnosis (hazard ratio, 0.043) and over the complete course of follow-up (hazard ratio, 0.098; both p<0.001). No associations with specific intrinsic breast cancer subtypes were found. Our data suggest that the determination of intracellular co-expression patterns of TRAIL-R1, TRAIL-R2, and TRAIL-R4 provides an innovative and robust method for risk stratification in breast cancer patients beyond conventional prognostic markers.Key messagesA total of 70% of breast cancer specimens show comparably high levels of intracellular TRAIL-Rs.Nuclear or cytoplasmic TRAIL-R co-expression occurs in the majority of tumors.A total of 25% of tumors show a heterogeneous expression of cytoplasmic or nuclear TRAIL-Rs.Patients with a heterogeneous TRAIL-R expression present with poor prognoses.Additive TRAIL-R-based risk stratification comprises different breast cancer subtypes.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Heilmann, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Vondung, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Borzikowsky, Christoph UNSPECIFIED orcid.org/0000-0002-5489-0032 UNSPECIFIED Szymczak, Silke UNSPECIFIED orcid.org/0000-0002-8897-9035 UNSPECIFIED Krueger, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Alkatout, Ibrahim UNSPECIFIED UNSPECIFIED UNSPECIFIED Wenners, Antonia UNSPECIFIED UNSPECIFIED UNSPECIFIED Bauer, Maret UNSPECIFIED UNSPECIFIED UNSPECIFIED Klapper, Wolfram UNSPECIFIED UNSPECIFIED UNSPECIFIED Roecken, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Maass, Nicolai UNSPECIFIED UNSPECIFIED UNSPECIFIED von Karstedt, Silvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Schem, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Trauzold, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-134085
DOI:	10.1007/s00109-019-01805-w
Journal or Publication Title:	J. Mol. Med.
Volume:	97
Number:	8
Page Range:	S. 1155 - 1168
Date:	2019
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-1440
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DEATH RECEPTORS; PROGNOSTIC VALUE; LIGAND TRAIL; APOPTOSIS; EXPRESSION; CELLS; ENDOCYTOSIS; METASTASIS; RESISTANCE; SURVIVAL Multiple languages Genetics & Heredity; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13408