title: β-catenin-independent WNT signaling and Ki67 in contrast to the estrogen receptor status are prognostic and associated with poor prognosis in breast cancer liver metastases.
abstract: Liver metastasis development in breast cancer patients is common and confers a poor prognosis. So far, the prognostic significance of surgical resection and clinical relevance of biomarker analysis in metastatic tissue have barely been investigated. We previously demonstrated an impact of WNT signaling in breast cancer brain metastasis. This study aimed to investigate the value of established prognostic markers and WNT signaling components in liver metastases. Overall N = 34 breast cancer liver metastases (with matched primaries in 19/34 cases) were included in this retrospective study. Primaries and metastatic samples were analyzed for their expression of the estrogen (ER) and progesterone receptor, HER-2, Ki67, and various WNT signaling-components by immunohistochemistry. Furthermore, β-catenin-dependent and -independent WNT scores were generated and analyzed for their prognostic value. Additionally, the influence of the alternative WNT receptor ROR on signaling and invasiveness was analyzed in vitro. ER positivity (HR 0.09, 95 % CI 0.01-0.56) and high Ki67 (HR 3.68, 95 % CI 1.12-12.06) in the primaries had prognostic impact. However, only Ki67 remained prognostic in the metastatic tissue (HR 2.46, 95 % CI 1.11-5.44). Additionally, the β-catenin-independent WNT score correlated with reduced overall survival only in the metastasized situation (HR 2.19, 95 % CI 1.02-4.69, p = 0.0391). This is in line with the in vitro results of the alternative WNT receptors ROR1 and ROR2, which foster invasion. In breast cancer, the value of prognostic markers established in primary tumors cannot directly be translated to metastases. Our results revealed β-catenin-independent WNT signaling to be associated with poor prognosis in patients with breast cancer liver metastasis.
authors: Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany.|Department of Medical Statistics, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Annalen
authors: A
authors: Bleckmann
authors: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Lena-Christin
authors: LC
authors: Conradi
authors: Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Kerstin
authors: K
authors: Menck
authors: Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Nadine Annette
authors: NA
authors: Schmick
authors: Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Antonia
authors: A
authors: Schubert
authors: Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Eva
authors: E
authors: Rietkötter
authors: Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Jetcy
authors: J
authors: Arackal
authors: Institute of Pathology, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Peter
authors: P
authors: Middel
authors: Department Biology, Developmental Biology, Friedrich-Alexander University Erlangen-Nürnberg, 91058, Erlangen, Germany.
authors: Alexandra
authors: A
authors: Schambony
authors: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Torsten
authors: T
authors: Liersch
authors: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Kia
authors: K
authors: Homayounfar
authors: Department of Medical Statistics, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Tim
authors: T
authors: Beißbarth
authors: Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Florian
authors: F
authors: Klemm
authors: Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany.
authors: Claudia
authors: C
authors: Binder
authors: Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany. tobias.pukrop@klinik.uni-regensburg.de.|Clinic for Internal Medicine III, Hematology and Medical Oncology, University Regensburg, 93053, Regensburg, Germany. tobias.pukrop@klinik.uni-regensburg.de.
authors: Tobias
authors: T
authors: Pukrop
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000096:biosynthesis* / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D019394:Ki-67 Antigen; D051176:beta Catenin; C078716:ROR1 protein, human; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors
keywords: Breast cancer; Metastasis; Prognostic score; WNT signaling