Stem Cells , Tissue Engineering and Hematopoietic Elements Wnt /-Catenin Pathway Activation Is Enriched in Basal-Like Breast Cancers and Predicts Poor Outcome

Although Wnt/ -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 -catenin subcellular localization. We demonstrate that nuclear and cytosolic accumulation of -catenin, a read-out of Wnt pathway activation, was enriched in basal-like breast cancers. In contrast, membrane-associated -catenin was observed in all breast cancer subtypes, and its expression decreased with tumor progression. Moreover, nuclear and cytosolic localization of -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 -catenin was associated with a poor outcome and is more frequently observed in tumors from black patients. In addition, -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/ -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. (Am J Pathol 2010, 176:2911–2920; DOI: 10.2353/ajpath.2010.091125) The Wnt/ -catenin pathway was first implicated in mammary tumorigenesis when the Int-1 integration site of the mouse mammary tumor virus was identified as the mammalian homolog of the Drosophila Wingless polarity morphogen. To reflect this homology, Int-1 was renamed Wnt-1, and its overexpression in the mammary epithelium was found to be sufficient for mammary tumorigenesis. Activation of the pathway by Wnt binding to its Fzd and FRP5/6 coreceptors prevents phosphorylation and degradation of -catenin, the major pathway effector, by the GSK3 /APC/axin destruction complex. Subsequent cytosolic and nuclear -catenin accumulation and binding to TCF transcription factors results in the regulation of target genes governing proliferation, survival, and matrix remodeling. Dysregulation of several other components of the Wnt/ -catenin pathway, including overexpression of a stabilized mutant of -catenin and mutation of Apc, results in mammary tumorigenesis in mouse models. Moreover, activation of this pathway is associated with both embryonic and postnatal mammary development in vivo, suggesting that its regulation is critical for proper mammary epithelial homeostasis. Despite these strong data in mouse models, Wnt pathway involvement in human breast cancer has not been clearly established. Pathway dysregulation, through expression of Wnts and secreted Wnt antagonists or APC inactivation, has been observed in human breast cancers. With respect to -catenin itself, nuclear -catenin has been observed in as many as 63% of breast cancers. Importantly, Hung and colleagues reported that nuclear staining of -catenin and overexpression of the -catenin target cyclin D1 was associated with a poorer