Abstract
Breast cancer is the leading cause of cancer-related deaths in women; however, its underlying etiology remains largely unknown. In this study, we systematically analyzed breast cancer tissues using comprehensive iTRAQ labeled quantitative proteomics, identifying 841 differentially expressed proteins (474 and 367 significantly over- and under-expressed, respectively), which were annotated by protein domain analysis. All the heat shock proteins identified were upregulated in breast cancer tissues; Hsp90 upregulation was also validated by RT-qPCR and immunohistochemistry, and high Hsp90 protein levels correlated with poorer survival. Hsp90AA1 overexpression promoted MDA-MB-231 cell proliferation, whilst BJ-B11, an Hsp90 inhibitor, hampered their invasion, migration, and proliferation in a time and dose-dependent manner and induced cell cycle arrest and apoptosis. BJ-B11 inhibited the expression of epithelial-mesenchymal transition (EMT) marker in MDA-MB-231 cells, whereas Hsp90AA1 promoted its expression. Moreover, BJ-B11 inhibited tumor growth in xenograft model. Altogether, Hsp90 activation is a risk factor in breast cancer patients, and BJ-B11 could be used to treat breast cancer.
Highlights
Breast cancer is the most frequently diagnosed cancer in women [1], and its incidence has increased in most developing countries over the past few decades [1, 2]
We investigated whether heat shock protein 90 (Hsp90) was associated with breast cancer and whether BJ-B11 affected the functions of breast cancer cells
We performed tissue microarray analysis, finding that Hsp90 protein levels increased in breast cancer tissue (P = 0.014; Figure 2A and Table S4)
Summary
Breast cancer is the most frequently diagnosed cancer in women [1], and its incidence has increased in most developing countries over the past few decades [1, 2]. Patients with breast cancer have a high 5-year survival rate following treatment, the survival rate decreases rapidly for patients with more advanced disease [3,4,5]. Triple-negative breast cancers (TNBCs) account for 15% of all breast cancers and lack estrogen, progesterone, and ERBB2 receptor expression [6]. TNBCs are poorly differentiated, and there are no specific treatment guidelines for this breast cancer subgroup [7, 8]; biomarkers and more effective medical therapies are urgently required. Breast cancer is coordinately controlled by regulatory networks; understanding these networks could help identify candidates for the diagnosis, prediction, and therapy of breast cancer. Proteomics approaches are often used to acquire a comprehensive and quantitative profile of protein expression. Isobaric tags for relative and absolute quantitation (iTRAQ) is a novel and unbiased approach to simultaneously quantify relative protein abundance [9]; in particular, the method enables protein quantification during various developmental stages [10]
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