Abstract
BackgroundHOMER family scaffolding proteins (HOMER1-3) play critical roles in the development and progression of human disease by regulating the assembly of signal transduction complexes in response to extrinsic stimuli. However, the role of HOMER protein in breast cancer remains unclear.MethodsHOMER3 expression was examined by immunohistochemistry in breast cancer patient specimens, and its significance in prognosis was assessed by Kaplan–Meier survival analysis. The effects of HOMER3 in growth factor-induced β-Catenin activation were analyzed by assays such as TOP/FOP flash reporter, tyrosine phosphorylation assay and reciprocal immunoprecipitation (IP) assay. Role of HOMER3 in breast cancer metastasis was determined by cell function assays and mice tumor models.ResultsHerein, we find that, among the three HOMER proteins, HOMER3 is selectively overexpressed in the most aggressive triple negative breast cancer (TNBC) subtype, and significantly correlates with earlier tumor metastasis and shorter patient survival. Mechanismly, HOMER3 interacts with both c-Src and β-Catenin, thus providing a scaffolding platform to facilitate c-Src-induced β-Catenin tyrosine phosphorylation under growth factor stimulation. HOMER3 promotes β-Catenin nuclear translocation and activation, and this axis is clinically relevant. HOMER3 promotes and is essential for EGF-induced aggressiveness and metastasis of TNBC cells both in vitro and in vivo.ConclusionThese findings identify a novel role of HOMER3 in the transduction of growth factor-mediated β-Catenin activation and suggest that HOMER3 might be a targetable vulnerability of TNBC.
Highlights
Breast cancer incidence has increased steadily during the past decades and is currently the most common malignancies in females worldwide [1]
We find that HOMER3 uses its enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain to recognize c-Src and β-Catenin, providing a scaffolding platform to increase the efficiency of c-Src-mediated β-Catenin tyrosine phosphorylation and activation under growth factors
HOMER family proteins (HOMER1-3) are scaffolding proteins that regulate the assembly of signal transduction complexes in response to extrinsic stimuli
Summary
Breast cancer incidence has increased steadily during the past decades and is currently the most common malignancies in females worldwide [1]. There are four major subtypes of breast cancer: Luminal A, Luminal B, HER2 and Triple-negative breast cancer (TNBC). TNBC, defined by lack of clinicopathological expression of hormonal receptors and Her, is the most aggressive subtype. Liu et al J Hematol Oncol (2021) 14:6 that accounts for only 15% of incidence but approximate 30% of breast cancer-related deaths [2, 3]. TNBC could not be treated with endocrine or targeted therapy [4]. The field is in need of new biomarkers and therapeutic targets. The role of HOMER protein in breast cancer remains unclear
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