Abstract
BackgroundTriple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies.MethodsWe conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease.ResultsThe annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/β-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/β-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or β-catenin (functional read out of Wnt/β-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from β-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/β-catenin classifier had a greater risk of lung and brain, but not bone metastases.ConclusionThese data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways.
Highlights
Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies
Quebec samples came from an unselected patient population from a community hospital in Canada whereas the Georgia cohort was preferentially selected for TNBC
cDNA mediated annealing (DASL) expression of ESR1 and PGR were greater in Hormone receptor (HR) + as compared to TNBC and Human epidermal growth factor receptor 2 (HER2)+ subtypes, and likewise ERBB2 expression was higher in HER2+ samples compared to TNBC and HR + subtypes in all cohorts (Additional file 3: Figure S1G-L)
Summary
Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies. Stratification of breast cancer (BC) into distinct histological or molecular subtypes has clinical utility for prognosis of outcome and prediction of treatment [1]. Breast cancer subtypes based on clinical or molecular characteristics are typically referred to as hormone-receptor positive (HR+) or luminal, HER2-amplified, and triple negative (TN) or basal-like. The first comprehensive genomic analysis of a basal-like breast cancer was performed by using massively parallel sequencing technology [8]. Despite a few recent reports that indicated the involvement of certain genes/signaling molecules related to tumorigenic pathways [4,9,10,11] in these subsets, there remains an unmet need for an in-depth study to identify driver pathways in these closely associated subtypes of BC
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