BCAS2 Enhances Carcinogenic Effects of Estrogen Receptor Alpha in Breast Cancer Cells

Abstract

Estrogen receptor alpha (ERα) has an established role in breast cancer biology. Transcriptional activation by ERα is a multistep process modulated by coactivator and corepressor proteins. Breast Cancer Amplified Sequence 2 (BCAS2), is a poorly studied ERα coactivator. In this work, we characterize some of the mechanisms through which this protein increases ERα activity and how this promotes carcinogenic processes in breast cancer cells. Using protein-protein interaction and luciferase assays we show that BCAS2 interacts with ERα both in vitro and in vivo and upregulates transcriptional activation of ERα directly through its N-terminal region (AF-1) and indirectly through its C-terminal (AF-2) region, acting in concert with AF-2 interacting coactivators. Elevated expression of BCAS2 positively affects proliferation, clonogenicity and migration of breast cancer cells and directly activates ERα regulated genes which have been shown to play a role in tumor growth and progression. Finally, we used signal transduction pathway inhibitors to elucidate how BCAS2 is regulated in these cells and observed that BCAS2 is preferentially regulated by the PI3K/AKT signaling pathway. BCAS2 is an AF-1 coactivator of ERα whose overexpression promotes carcinogenic processes, suggesting an important role in the development of estrogen-receptor positive breast cancer.

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<p>ERα, A Key Target for Cancer Therapy: A Review</p>

“…69,71 In ER+ breast cancer, estrogen activates the PI3K/AKT/mTOR signaling pathway by associating with extra-nuclear ERα, which results in drug resistance and epithelial-to-mesenchymal transition (EMT) (Figure 3). 70,72 Targeting ERα reportedly causes changes in the expression of components of the PI3K/AKTprotein kinase Cα signaling pathway, resulting in cell apoptosis. 73 Also, the activation of ERα results in increased expression of the PI3K/AKT/NF-κB signaling pathway, leading to tumor invasion and metastasis in breast cancer.…”