WNT5B governs the phenotype of basal-like breast cancer by activating WNT signaling

Shaojie Jiang,Yanhua Zhang,Jihong Sun,Qing Ruan,Miaofeng Zhang,Jie Fang,Hui Chen,Tao Zhu,Fei Zhou,Xiaoming Yang,Weiping Zhou

doi:10.1186/s12964-019-0419-2

Abstract

BackgroundBreast cancer is the leading cause of cancer-related death in women worldwide. Metastatic disease remains the primary cause of death in patients with breast cancer. Basal-like breast cancer (BLBC) is associated with aggressive behavior, stem-like phenotype, high histological grade, poor clinical features, and high rates of recurrences and/or metastasis. However, the mechanism of BLBC phenotype shaping remains obscure.MethodsSeventeen normal breast/breast cancer cell lines were used for evaluating the breast cancer subtype-markers, WNT targets and constitutive components, and epithelial mesenchymal transition (EMT) markers analysis by western blot. One hundred and twenty formalin-fixed breast cancer tissues were used for immunohistochemistry (IHC) staining. Nine online platforms (cBioPortal, CCLE, GEPIA, etc.) were used for related analyses.ResultsWe identified Wnt5b as a key regulatory factor that governs the phenotype of BLBC by activating canonical and non-canonical WNT signaling. Wnt5b exhibited basal-like specificity in cells and clinical samples both at the mRNA and protein levels and also showed good correlation with basal-like phenotype at the mRNA level. Besides, Wnt5b was also a promising therapeutic target for LGK-974 treatment. In addition, we identified that CK1α was expressed at low levels in BLBC and that the activation of CK1α by pyrvinium was an alternative strategy for BLBC treatment.ConclusionsWnt5b is not only a diagnostic biomarker but also a potential therapeutic target of BLBC.Graphical abstract

Highlights

Breast cancer is the leading cause of cancer-related death in women worldwide
human epidermal growth factor receptor 2 (Her-2) as a marker for Her-2+ breast cancer; Progesterone Receptor (PR), estrogen receptor (ER), CK18 (Cytokeratin 18), FoxA1, and Anterior gradient homolog 2 (AGR2) (Anterior gradient 2) as markers of luminal breast cancer; CD44, Caveolin-1, Caveolin-2, Epidermal growth factor receptor (EGFR), CK5 (Cytokeratin 5), and Secreted protein acidic and rich in cysteine (SPARC) (Secreted protein acidic and cysteine-rich) as markers of Basal-like breast cancer (BLBC) were used for molecular typing
IHC staining showed that CK18, FoxA1, and AGR2 exhibited specificity for the luminal subtype, while Caveolin-1 exhibited specificity for the BLBC (Fig. 1c-e) in addition to the conventional makers, Her-2, ER, PR, Ki-67, EGFR, and CK-5/6 (Additional file 1: Figure S1b)

Summary

Introduction

Breast cancer is the leading cause of cancer-related death in women worldwide. Metastatic disease remains the primary cause of death in patients with breast cancer. Basal-like breast cancer (BLBC) is associated with aggressive behavior, stem-like phenotype, high histological grade, poor clinical features, and high rates of recurrences and/or metastasis. A previous study reported 51% luminal A, 16% luminal B, 7% Her-2+, 20% basal-like, and 6% normal-like breast cancers in 496 cases of invasive breast cancer [6]. BLBC is the second most common subtype after luminal A of invasive breast cancer. Previous studies demonstrated that BLBC cell lines expressed EMT-acquired markers such as Snail, vimentin, and N-cadherin, but lost EMTattenuated marker E-cadherin compared to luminal breast

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