Abstract 33: Calsequestrin 2 regulates proliferation, migration, and invasion in triple-negative breast cancer cells

Abstract

Triple-negative breast cancer (TNBC) is the most heterogeneous and aggressive breast tumor subtype defined by absence of receptor for estrogen, progesterone, or HER2. However, the biologic mechanism for TNBC phenotype is still unclear. Here, we show that expression of Calsequestrin 2 (CASQ2), a Ca2+-binding protein, correlates with increase of proliferation, migration, and invasion, suggesting that intracellular Ca2+ may contribute to tumor growth and metastatic phenotype. CASQ2 is the main Ca2+-binding protein inside the sarcoplasmic reticulum of cardiomyocytes. CASQ2 forms a complex with ryodine receptor 2 (RyR2) luminal calcium release channel in cardiac muscle. Ca2+ is a sequestor and regulator of diverse cellular processes, and specific Ca2+ channels play important roles in cell proliferation and invasiveness of cancers. To know the role of CASQ2 TNBC cells, we established CASQ2-overexpressing stable cells in Hs578T (Hs578T-CASQ2) using retrovirus. Stimulation with caffeine triggered the remarkable increase of intracellular calcium in Hs578T-CASQ2 cells; in addition, the basal level of calcium in cells had much higher amount of Hs578T-CASQ2 than Hs578T. By contrast, calcium chelator BAPTM/AM blocked CASQ2-induced calcium release. Hs578T-CASQ2 cells showed higher level of proliferation, migration and invasion rate compared to Hs578T, which indicated that overexpression of CASQ2 related with cellular functions. We also found that CASQ2 overexpression elevates extracellular signal-related kinase (ERK) expression. In epidermal growth factor (EGF)-treated cells, Hs578T-CASQ2 cells had higher phosphorylated ERK compared to Hs578T, leading to the expression of epithelial-mesenchymal transition (EMT) marker, vimentin. These results indicate that CASQ2 overexpression increases the level of calcium and induces cell proliferation, migration and invasion through ERK signaling. Our findings from this study show a possible cause of migration and invasiveness in breast cancer cells. Taken together, these findings demonstrate that CASQ2 could be a new therapeutic target for breast cancer. Citation Format: Ju Hee Kim, Bok sil Hong, Woohang Heo, Jong Min Han, Wonsik Han, Dong-Young Noh, Hyeong-Gon Moon. Calsequestrin 2 regulates proliferation, migration, and invasion in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 33.

Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy

“…Several FDA-approved anticancer agents (such as 5-fluorouracil, cisplatin, tamoxifen, paclitaxel, and doxorubicin) and drugs against other disease conditions (such as leflunomide, tolvaptan, and teriflunomide) can impact Ca 2+ signaling machinery [ 484 , 485 ]. Some of these drugs, formulated as prodrugs or nanocarrier loads, are under investigation as antagonists of cancer-promoting Ca 2+ signaling See Figure 12 [ 46 , 226 , 227 , 252 , 440 , 441 , 486 , 487 , 488 , 489 , 490 , 491 , 492 , 493 , 494 , 495 , 496 , 497 , 498 , 499 , 500 , 501 , 502 , 503 , 504 , 505 , 506 , 507 , 508 , 509 , 510 , 511 , 512 , 513 , 514 , 515 , 516 , 517 , 518 , 519 , 520 , 521 , 522 , 523 , …”

Comprehensive gene cluster analysis of head and neck squamous cell carcinoma TCGA RNA‐seq data defines B cell immunity‐related genes as a robust survival predictor

“…In addition, a recent study revealed that B cells are associated with survival and immunotherapy response in sarcoma, and both JCHAIN (also known as IGJ) and TNFRSF17 (encoding BCMA) in tumors may contribute to the improved prognosis 33 . Interestingly, majority of the eight genes in cluster_4 have been reported to be involved in arteriogenesis, 46 migration/invasion, and metastasis in head and neck cancers 47–49 or other tumors 50–53 . In addition, some of the genes may play opposite roles in different tumors.…”