The expression of high mobility group protein 3 (HMGB3) in breast cancer with emphasis on its role in lymphovascular invasion.

Lymphovascular invasion (LVI) is a common phenomenon in breast cancer (BC), and it is correlated to poor outcome. However, the biomarkers that influence the development of LVI remain to be defined. Through rigorous bioinformatics analyses, high mobility group protein 3 (HMGB3) was revealed as a driver gene that is associated with the presence of LVI. The purpose of this study was to further investigate the role of HMGB3 in the pathogenesis of LVI in BC. In vitro functional assays were performed to investigate the effect of HMGB3 silencing on cell proliferation, migration, adherence and transmigration of BC cell lines with dermal lymphatic endothelial cells (DLECs) and human vascular endothelial cells (HUVECs). The correlation of HMGB3 expression with clinicopathological parameters was also assessed at the transcriptomic and the proteomic levels using large BC cohorts with well-characterised LVI status. Silencing HMGB3 reduced cell proliferation, migration, adherence and transmigration across endothelial cell lines. At the mRNA and protein levels, high HMGB3 expression was significantly correlated with LVI-positivity, higher tumour grade, lymph nodal stage, hormone receptor negativity, HER2 positivity and poor outcome. Moreover, high HMGB3 expression was an independent predictor of shorter breast cancer-specific survival. HMGB3 plays an oncogenic function and contributes to the development of LVI in BC. Results warrant further investigation as a potential target to inhibit LVI in BC.

Prognostic significance of heat shock protein 90AA1 (HSP90α) in invasive breast cancer.

AIMS: The mechanisms that drive breast cancer (BC) progression and poor outcome are not fully understood. The human heat shock protein 90 alpha family class A member 1 (HSP90α) encoded by the HSP90ΑA1 gene has a vital role in cellular responses to stress and is implicated in the development and progression of many cancers. The current study aims to explore the clinical and prognostic importance of HSP90α in BC. METHODS: The Molecular Taxonomy of Breast Cancer International Consortium (n=1980); The Cancer Genome Atlas (n=1097) and the Breast Cancer Gene-Expression Miner (Bc-GenExMiner) BC datasets (n=5056) were used to evaluate HSP90ΑA1 mRNA expression. HSP90α protein expression was further assessed using immunohistochemistry in a large (n=911) well-characterised BC series. The association between mRNA and protein expressions with other clinicopathological parameters and outcome was analysed. RESULTS: High expression of HSP90ΑA1 both at the mRNA and protein levels was significantly associated with characteristics of BC poor prognosis, including high grade, lymphovascular invasion, poor Nottingham Prognostic Index and positive expression of p53 and PIK3CA. Outcome analysis revealed that high HSP90α protein expression is an independent predictor of shorter BC-specific survival. CONCLUSION: HSP90α can be used as a potential prognostic marker in BC. Further mechanistic studies are warranted to determine the underlying molecular mechanisms mediated by HSP90α in BC.