TY - JOUR
T1 - Heterogeneous intracellular TRAIL-receptor distribution predicts poor outcome in breast cancer patients
AU - Heilmann, Thorsten
AU - Vondung, Florian
AU - Borzikowsky, Christoph
AU - Szymczak, Silke
AU - Krüger, Sandra
AU - Alkatout, Ibrahim
AU - Wenners, Antonia
AU - Bauer, Maret
AU - Klapper, Wolfram
AU - Röcken, Christoph
AU - Maass, Nicolai
AU - von Karstedt, Silvia
AU - Schem, Christian
AU - Trauzold, Anna
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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 5 years 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 messages: A 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.
AB - 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 5 years 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 messages: A 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.
UR - http://www.scopus.com/inward/record.url?scp=85067296909&partnerID=8YFLogxK
U2 - 10.1007/s00109-019-01805-w
DO - 10.1007/s00109-019-01805-w
M3 - Journal articles
C2 - 31183506
AN - SCOPUS:85067296909
SN - 0946-2716
VL - 97
SP - 1155
EP - 1167
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 8
ER -
