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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-016-9780-3) contains supplementary material, which is available to authorized users.

High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia

“…A variety of different cancers have been found to express ROR1. 23 To date, high-level expression of ROR1 has been found to have adverse prognostic significance for patients with breast cancer, [24][25][26][27] ovarian cancer, 28,29 melanoma, 30 or Ewing sarcoma. 31 Moreover, high-level expression of ROR1 also has been associated with higher levels of AKT activation, 24,30,32,33 consistent with the notion that ROR1 signaling leading to activation of AKT may serve as a driver, not just in CLL, but also in other malignancies.…”

The expression and biological function of the PHF2 gene in breast cancer

“…23 As we all know, Ki67 is a good marker of cell proliferation in a variety of tumors and lymph node metastasis indicates high invasion and migration of tumors, which can be used for prognostic assessments of patients with cancer. [24][25][26][27][28][29] Further prognostic analysis of the Kmplot online database conrmed this point which showed that the breast cancer patients with low PHF2 expression frequently have shorter OS and RFS compared to the high expression group. In further studies, we will assess the prognosis of different histological types of breast cancer with a large sample and a longer followup period.…”

Reduced camptothecin sensitivity of estrogen receptor‐positive human breast cancer cells following exposure to di(2‐ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes

“…This way they are not favorable to form the Top1‐DNA cleavage complex. Second, breast cancer cells are reported to utilize aberrant Wnt signaling to overcome apoptosis . Owing to epigenetic activation of Wnt signaling, DEHP‐exposed MCF‐7 cells might escape from the cytotoxic effects of CPT.…”

“…There are multiple oncogenic signaling pathways that contribute to estrogen‐induced therapeutic failures, including the activation of PI3K/Akt, Wnt/β‐catenin, NF‐κB, MAPK/ERK pathways and a set of receptors such as human epidermal growth factor receptor‐2 (HER2), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR) and insulin‐like growth factor 1 receptor (IGF1R) . However, it is difficult to rule out the possibility that the acquired drug resistance in cancer is triggered by epigenetic regulation.…”