p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading

Abstract

BackgroundTraditional prognostic indicators of breast cancer, i.e. lymph node diffusion, tumor size, grading and estrogen receptor expression, are inadequate predictors of metastatic relapse. Thus, additional prognostic parameters appear urgently needed. Individual oncogenic determinants have largely failed in this endeavour. Only a few individual tumor growth drivers, e.g. mutated p53, Her-2, E-cadherin, Trops, did reach some prognostic/predictive power in clinical settings. As multiple factors are required to drive solid tumor progression, clusters of such determinants were expected to become stronger indicators of tumor aggressiveness and malignant progression than individual parameters. To identify such prognostic clusters, we went on to coordinately analyse molecular and histopathological determinants of tumor progression of post-menopausal breast cancers in the framework of a multi-institutional case series/case-control study.MethodsA multi-institutional series of 217 breast cancer cases was analyzed. Twenty six cases (12 %) showed disease relapse during follow-up. Relapsed cases were matched with a set of control patients by tumor diameter, pathological stage, tumor histotype, age, hormone receptors and grading. Histopathological and molecular determinants of tumor development and aggressiveness were then analyzed in relapsed versus non-relapsed cases. Stepwise analyses and model structure fitness assessments were carried out to identify clusters of molecular alterations with differential impact on metastatic relapse.Resultsp53, Bcl-2 and cathepsin D were shown to be coordinately associated with unique levels of relative risk for disease relapse. As many Ras downstream targets, among them matrix metalloproteases, are synergistically upregulated by mutated p53, whole-exon sequence analyses were performed for TP53, Ki-RAS and Ha-RAS, and findings were correlated with clinical phenotypes. Notably, TP53 insertion/deletion mutations were only detected in relapsed cases. Correspondingly, Ha-RAS missense oncogenic mutations were only found in a subgroup of relapsing tumors.ConclusionsWe have identified clusters of specific molecular alterations that greatly improve prognostic assessment with respect to singularly-analysed indicators. The combined analysis of these multiple tumor-relapse risk factors promises to become a powerful approach to identify patients subgroups with unfavourable disease outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2713-3) contains supplementary material, which is available to authorized users.

Overexpression Cathepsin D Contributes to Perineural Invasion of Salivary Adenoid Cystic Carcinoma

“…These results were consistent with the previous studies ( 27 ). In breast cancer, Achour et al and Guerra et al found that CTSD was a marker of poor prognosis and was associated with metastatic relapse of breast cancer ( 14 , 16 ). Knopfová et al reported that the elevation of CTSD expression mediated the invasion and metastasis of breast cancer in an organ-specific manner ( 28 ), and Anantaraju et al identified that CTSD inhibitors might be used as potential therapeutics for breast cancer treatment ( 29 ).…”

“…Cathepsin D (CTSD), a broadly expressed peptidase, belongs to the family of lysosomal aspartic protease, whose most general and basic function is intracellular catabolism in lysosomal compartments ( 12 , 13 ). Besides, it also has been implicated as an important factor in many physiological and pathological processes, such as neovascularization of endothelial progenitor cells, hormone and antigen processing, cell growth, and tissue homeostasis, the metabolic degradation of proteins and peptides, inflammation, and atherosclerosis ( 14 – 16 ). Recently, a wide array of studies documented that CTSD facilitates invasion and dissemination of tumors via different mechanisms related to its proteolytic activities ( 17 – 19 ), and CTSD was also detected in SACC ( 20 ).…”

Co-Expression of Androgen Receptor and Cathepsin D Defines a Triple-Negative Breast Cancer Subgroup with Poorer Overall Survival

“…Cath-D, p53, and BCL-2, assessed by IHC, are prognostic indicators of BC metastatic spreading [39]. Cath-D quantified by cytosolic assay in primary BC is a well-established marker of poor prognosis independently of the ER status [20,21].…”

TIPE3 protein promotes breast cancer metastasis through activating AKT and NF-κB signaling pathways

“…Moreover, we found that the expression of TIPE3 was positively correlated with HER2 expression. Overexpression of HER2, Ki67 and p53 are found in 20∼30% of breast cancer patients and is associated with poor prognosis and relapse [ 35 – 38 ]. These results demonstrate that elevated expression of TIPE3 may be correlated with the increase of malignancy degree in breast cancer tissue and serve as a novel biomarker for the diagnosis of the earliest possible stage and response to therapy.…”