Wnt/β-Catenin Pathway Activation Is Enriched in Basal-Like Breast Cancers and Predicts Poor Outcome

Abstract

Although Wnt/beta-catenin pathway activation has been implicated in mouse models of breast cancer, there is contradictory evidence regarding its importance in human breast cancer. In this study, invasive and in situ breast cancer tissue microarrays containing luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)(+)/ER(-) and basal-like breast cancers were analyzed for beta-catenin subcellular localization. We demonstrate that nuclear and cytosolic accumulation of beta-catenin, a read-out of Wnt pathway activation, was enriched in basal-like breast cancers. In contrast, membrane-associated beta-catenin was observed in all breast cancer subtypes, and its expression decreased with tumor progression. Moreover, nuclear and cytosolic localization of beta-catenin was associated with other markers of the basal-like phenotype, including nuclear hormone receptor and HER2 negativity, cytokeratin 5/6 and vimentin expression, and stem cell enrichment. Importantly, this subcellular localization of beta-catenin was associated with a poor outcome and is more frequently observed in tumors from black patients. In addition, beta-catenin accumulation was more often observed in basal-like in situ carcinomas than other in situ subtypes, suggesting that activation of this pathway might be an early event in basal-like tumor development. Collectively, these data indicate that Wnt/beta-catenin activation is an important feature of basal-like breast cancers and is predictive of worse overall survival, suggesting that it may be an attractive pharmacological target for this aggressive breast cancer subtype.

Molecular insights on basal-like breast cancer

“…Other alterations such as Wnt pathway activation has been observed in BLBC [24]. This study reported cytoplasmic and nuclear accumulation of -catenin in BLBC, and suggested that β-catenin could be a valuable therapeutic target for this subtype [24].…”

“…This study reported cytoplasmic and nuclear accumulation of -catenin in BLBC, and suggested that β-catenin could be a valuable therapeutic target for this subtype [24]. Nevertheless there is strong evidence of stabilization of β-catenin protein in a majority of human breast tumors, and mouse model systems clearly demonstrate that activated Wnt signaling can promote mammary tumorigenesis [25].…”

Prognostic Value of β-catenin Expression in Breast Cancer Patients: a Meta-analysis

“…Alteration of molecular biological markers in tumor tissues has become an important part in predicting the prognosis of patients with BC and seemed more specific than markers currently used in clinical such as TNM stage, weight loss and lymph node metastasis. There are many reports about the prognostic significance of β-catenin in BC (Lin et al, 2000;Gillett et al, 2001;Lim and Lee, 2002;Chung et al, 2004;Dolled-Filhart et al, 2006;Nakopoulou et al, 2006;Park et al, 2007;Fanelli et al, 2008;Paredes et al, 2008;Khramtsov et al, 2010;Kim et al, 2010;Logullo et al, 2010;Lopez-Knowles et al, 2010;Geyer et al, 2011;Cheng et al, 2012;Mukherjee et al, 2012;Xu et al, 2012;Ho et al, 2013;Pang et al, 2013;Weissenbacher et al, 2013;Li et al, 2014). However, results were inconsistent.…”

Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

“…Basal-like cancers also demonstrate some overlap with triple-negative cancers [4]. Different subtypes can be distinguished molecularly by gene expression signatures, such as expression of cytokeratins 5, 6, and 14 by basal-like cancers, and expression of cytokeratins 8 and 18 by luminal cancers [5, 8]. Other minor classifications, such as the claudin lo and claudin hi subgroups, have been identified, but their clinical significance remains to be determined [9].…”

“…Moreover, an understanding of these origins may provide insight into classification of cancer and may allow for better prognosis assessment [54]. Further complicating these ideas is that, within each tissue type, there may be particular cellular subtypes that give rise to stem-like tumor cells, such as the basal-like subgroup of breast cancer [5]. Basal-like breast cancers have been found to demonstrate aberrant activation of the canonical Wnt pathway, and Wnt signaling is a critical intracellular signal transduction pathway in stem cell biology [5].…”