Immunohistochemical expression of epithelial and stromal immunomodulatory signalling molecules is a prognostic indicator in breast cancer

Abstract

BackgroundThe immune system has paradoxical roles during cancer development and the prognostic significance of immune modulating factors is controversial. The aim of this study was to determine the expression of cyclooxygenase 2 (COX-2), transforming growth factor-beta (TGF- beta), interleukin-10 (IL-10) and their prognostic significance in breast cancers. Ki67 was included as a measure of growth fraction of tumor cells.MethodsOn immunohistochemical stained slides from 38 breast cancer patients, we performed digital video analysis of tumor cell areas and adjacent tumor stromal areas from the primary tumors and their corresponding lymph node metastases. COX-2 was recorded as graded staining intensity.ResultsThe expression of TGF-beta, IL-10 and Ki67 were recorded in tumor cell areas and adjacent tumor stromal areas. In both primary tumors and metastases, the expression of COX-2 was higher in the tumor stromal areas than in the tumor cell areas (both P < 0.001). High stromal staining intensity in the primary tumors was associated with a 3.9 (95% CI 1.1-14.2) times higher risk of death compared to the low staining group (P = 0.036). The expression of TGF-beta was highest in the tumor cell areas of both primary tumors and metastases (both P < 0.001). High stromal expression of TGF-beta was associated with increased mortality. For IL-10, the stromal expression was highest in the primary tumors (P < 0.001), whereas in the metastases the expression was highest in tumor cell areas (P < 0.001). High IL-10 expression in tumor- and stromal cell areas of primary tumors predicted mortality. Ki67 was higher expressed in tumor stromal areas of the metastases, and in tumor cell areas of the primary tumors (P < 0.001). Ki67 expression in tumor cell areas and stromal areas of the metastases was independently associated with breast cancer mortality.ConclusionsStromal expression of COX-2, TGF-beta and Ki67 may facilitate tumor progression in breast cancer.

Clinicopathological significance of caspase-3 and Ki-67 expression in canine mammary gland tumours

“…For Ki-67 expression there was a statistically significant association with larger tumour size, histological type, mitotic index, nuclear grade, histological grade of malignancy, and the presence of lymph node metastasis. Similar results have already been described by other researchers for human and canine mammary tumours (Labelle et al, 2004;De Matos et al, 2006;Richardsen et al, 2012;Santos et al, 2013).…”

“…Although the precise function of this protein is uncertain, its tight association with the cell-cycle regulation phase and its short half-life render this protein a valid marker for the assessment of the growth fraction of neoplastic cells (Klopfleisch et al, 2011;Inwald et al, 2013;Ricciardi et al, 2015). The high Ki-67 index has been positively correlated with metastasis, death from neoplasia, low disease-free survival rates, and low overall survival rates in both humans and dogs (Labelle et al, 2004;De Matos et al, 2006;Richardsen et al, 2012;Santos et al, 2013).…”

“…Uncontrolled proliferation is an already known hallmark of malignancy in human and canine mammary tumours, and several studies have focused on this topic (Labelle et al, 2004;De Matos et al, 2006;Richardsen et al, 2012;Santos et al, 2013). Ki-67 is a non-histone nuclear protein associated with cellular proliferation and is usually detected with MIB-1 antibody.…”

Breast Carcinoma–associated Fibroblasts Share Similar Biomarker Profiles in Matched Lymph Node Metastasis

“…Our levels of TGFb1 and CXCR4 expression in primary fibroblasts are consistent with those found in previous studies. 14,31,32 TGFb1 has been shown to activate PI3K, leading to AKT activation in diverse cell systems. 20 We have found that TGFb1, CXCR4, and p-AKT expression in fibroblasts correlated well between primaries and the involved lymph nodes.…”

CCL2/CCR2 Chemokine Signaling Coordinates Survival and Motility of Breast Cancer Cells through Smad3 Protein- and p42/44 Mitogen-activated Protein Kinase (MAPK)-dependent Mechanisms

“…However, there are conflicting reports regarding the prognostic significance of TGF-␤ expression in breast tumors (81)(82)(83). TGF-␤ expression in breast tumors may be dependent on several factors including the degree of stromal reactivity and clinical subtype (84).…”