Targeting serum response factor as a novel therapeutic approach for triple-negative breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12560-e12560
Author(s):  
Maria Prencipe ◽  
Claudia Aura Gonzalez ◽  
Niamh Russell ◽  
William M. Gallagher ◽  
John Crown
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cell Migration ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Serum Response Factor ◽  
P Value ◽  
Response Factor ◽  
Serum Response

e12560 Background: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer (BC) which lacks estrogen receptor, progesterone receptor and HER2 amplification. Due to the fact that up to 50% of TNBC express AR and that AR expression has been associated with poor prognosis, targeting AR in TNBC is attracting increasing interest. However, although targeting AR in prostate cancer results in initial response, resistance eventually develops, resulting in treatment failure. We previously identified Serum Response Factor (SRF) as an important transcription factor in a cellular model of castrate-resistant prostate cancer. We showed a relationship between SRF and AR which potentially plays a role in the resistance to AR-targeted therapy. Therefore, we hypothesise that AR resistance mechanisms could be bypassed by targeting SRF, singly or in combination with AR-inhibitors. Methods: In this study three TNBC cell lines with different SRF/ AR levels were selected to investigate the effect of SRF inhibition on cell viability, cell migration and cell invasion. Immunohistochemistry was used to assess SRF expression in 3 BC TMAs: TMA1 (n = 144) and TMA2 (n = 512) with different subtypes of BC and TMA3 with 138 TNBC patients. Results: MTT assays showed response to CCG1423 in the two cell lines positive for SRF (MDA-MB-231 and HS578t) with IC50 values of 20 uM, while MDA-MB-453 (SRF negative) did not respond (IC50 > 80uM). In addition, a synergistic effect on cell viability was demonstrated when CCG1423 was used in combination with MDV3100. Scratch assays to assess cell migration showed a slower gap-closure post- CCG1423 treatment compared to controls. In addition, CCG1423 treatment significantly reduced both cell lines’ ability to invade by approximately 50% at 48 hours post-treatment (p < 0.05). Analysis of SRF expression in clinical samples showed higher SRF protein expression in TNBC vs. non-TNBC patients. In addition, one TMA (n = 144) showed that higher SRF expression was associated with shorter overall survival (HR 1.99 [CI (1.02, 3.87)], P value 0.039) and shorter disease specific survival (HR 2.93 [CI (1.19, 7.21)], P value 0.014). Conclusions: Our data support the rationale for using SRF as an alternative target to AR, alone or in combination with AR-antagonists.

scholarly journals Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Pradip Shahi Thakuri ◽  
Megha Gupta ◽  
Sunil Singh ◽  
Ramila Joshi ◽  
Eric Glasgow ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Protein Kinases ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Tnbc Cell

Abstract Background Cell migration and invasion are essential processes for metastatic dissemination of cancer cells. Significant progress has been made in developing new therapies against oncogenic signaling to eliminate cancer cells and shrink tumors. However, inherent heterogeneity and treatment-induced adaptation to drugs commonly enable subsets of cancer cells to survive therapy. In addition to local recurrence, these cells escape a primary tumor and migrate through the stroma to access the circulation and metastasize to different organs, leading to an incurable disease. As such, therapeutics that block migration and invasion of cancer cells may inhibit or reduce metastasis and significantly improve cancer therapy. This is particularly more important for cancers, such as triple negative breast cancer, that currently lack targeted drugs. Methods We used cell migration, 3D invasion, zebrafish metastasis model, and phosphorylation analysis of 43 protein kinases in nine triple negative breast cancer (TNBC) cell lines to study effects of fisetin and quercetin on inhibition of TNBC cell migration, invasion, and metastasis. Results Fisetin and quercetin were highly effective against migration of all nine TNBC cell lines with up to 76 and 74% inhibitory effects, respectively. In addition, treatments significantly reduced 3D invasion of highly motile TNBC cells from spheroids into a collagen matrix and their metastasis in vivo. Fisetin and quercetin commonly targeted different components and substrates of the oncogenic PI3K/AKT pathway and significantly reduced their activities. Additionally, both compounds disrupted activities of several protein kinases in MAPK and STAT pathways. We used molecular inhibitors specific to these signaling proteins to establish the migration-inhibitory role of the two phytochemicals against TNBC cells. Conclusions We established that fisetin and quercetin potently inhibit migration of metastatic TNBC cells by interfering with activities of oncogenic protein kinases in multiple pathways.

scholarly journals Androgen-responsive Serum Response Factor target genes regulate prostate cancer cell migration

2013 ◽  
Vol 34 (8) ◽  
pp. 1737-1746 ◽  
Author(s):  
A. R. Verone ◽  
K. Duncan ◽  
A. Godoy ◽  
N. Yadav ◽  
A. Bakin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Migration ◽  
Cancer Cell ◽  
Target Genes ◽  
Serum Response Factor ◽  
Prostate Cancer Cell ◽  
Response Factor ◽  
Cancer Cell Migration ◽  
Serum Response

USP2 promotes cell migration and invasion in triple negative breast cancer cell lines

Tumor Biology ◽  
2015 ◽  
Vol 36 (7) ◽  
pp. 5415-5423 ◽  
Author(s):  
Qing Qu ◽  
Yan Mao ◽  
Gang Xiao ◽  
Xiaochun Fei ◽  
Jinglong Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines ◽  
Cell Migration And Invasion

scholarly journals Overexpression of SERPINA3 promotes tumor invasion and migration, epithelial-mesenchymal-transition in triple-negative breast cancer cells

Breast Cancer ◽  
2021 ◽  
Author(s):  
Yingzi Zhang ◽  
Jiao Tian ◽  
Chi Qu ◽  
Yang Peng ◽  
Jinwei Lei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Tnbc Cell

Abstract Background Recent studies have indicated that serpin peptidase inhibitor, clade A, member 3 (SERPINA3) is a potential marker associated with tumor progression, which connoted that SERPINA3 is related to malignant phenotypes in cancer. However, the biological function of SERPINA3 in breast cancer (BC) remains unclear. Methods Bioinformatics data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Immunohistochemical staining (IHC) was conducted to determine SERPINA3 expression. With strong aggressive abilities, triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, BT549 and MDA-MB-436) were obtained to examine SERPINA3 expression and functions. Wound healing and Transwell assays were performed to measure cell migration and invasion. Cell Counting Kit-8 (CCK-8) assay was conducted to detect cell proliferation abilities and cell viabilities. Results SERPINA3 was upregulated in BC tissues. Functional assays suggested that overexpression of SERPINA3 significantly promoted cell proliferation, where migration and invasion of TNBC cells were accelerated. Knockdown of SERPINA3 had the opposite effects. These results causing by overexpression of SERPINA3 were also confirmed in non-TNBC cell lines. Overexpression of SERPINA3 remarkably enhanced the epithelial–mesenchymal transition (EMT) by upregulating the EMT markers and EZH2. In addition, the overexpression of SERPINA3 reduced the sensitivity of TNBC cells to cisplatin. Conclusion SERPINA3 can regulate the migration, invasion and EMT of TNBC cells and increased expression of SERPINA3 confers resistance to cisplatin in TNBC cells. We discern it is required for the regulation of BC progression and is a critical target for the clinical treatment of BC.

scholarly journals Syndecan-1 Promotes Angiogenesis in Triple-Negative Breast Cancer through the Prognostically Relevant Tissue Factor Pathway and Additional Angiogenic Routes

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2318
Author(s):  
Eyyad Nassar ◽  
Nourhan Hassan ◽  
Eslam A. El-Ghonaimy ◽  
Hebatallah Hassan ◽  
Mahmoud Salah Abdullah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tissue Factor ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Network Formation ◽  
Umbilical Vein ◽  
Poor Survival ◽  
Altered Expression ◽  
Basal Breast Cancer

Triple-negative breast cancer (TNBC) is characterized by increased angiogenesis, metastasis, and poor survival. Dysregulation of the cell surface heparan sulfate proteoglycan and signaling co-receptor Syndecan-1 is linked to poor prognosis. To study its role in angiogenesis, we silenced Syndecan-1 in TNBC cell lines using a 3D human umbilical vein endothelial cell (HUVEC) co-culture system. Syndecan-1 siRNA depletion in SUM-149, MDA-MB-468, and MDA-MB-231 cells decreased HUVEC tubule network formation. Angiogenesis array revealed reduced VEGF-A and tissue factor (TF) in the Syndecan-1-silenced secretome. qPCR independently confirmed altered expression of F3, F7, F2R/PAR1, F2RL1/PAR2, VEGF-A, EDN1, IGFBP1, and IGFBP2 in SUM-149, MDA-MB-231, and MDA-MB-468 cells. ELISA revealed reduced secreted endothelin-1 (SUM-149, MDA-MB-468) and TF (all cell lines) upon Syndecan-1 depletion, while TF pathway inhibitor treatment impaired angiogenesis. Survival analysis of 3951 patients demonstrated that high expression of F3 and F7 are associated with better relapse-free survival, whereas poor survival was observed in TNBC and p53 mutant basal breast cancer (F3) and in ER-negative and HER2-positive breast cancer (F2R, F2RL1). STRING protein network analysis revealed associations of Syndecan-1 with VEGF-A and IGFBP1, further associated with the TF and ET-1 pathways. Our study suggests that TNBC Syndecan-1 regulates angiogenesis via the TF and additional angiogenic pathways and marks its constituents as novel prognostic markers and therapeutic targets.

scholarly journals Meroterpenoids From Ganoderma lucidum Mushrooms and Their Biological Roles in Insulin Resistance and Triple-Negative Breast Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Jiao-Jiao Zhang ◽  
Dai-Wei Wang ◽  
Dan Cai ◽  
Qing Lu ◽  
Yong-Xian Cheng
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Line ◽  
Triple Negative Breast Cancer ◽  
Ganoderma Lucidum ◽  
Triple Negative ◽  
Raw Materials ◽  
Biological Evaluation ◽  
C2c12 Cells ◽  
Dependent Manner

Ganoderma fungi as popular raw materials of numerous functional foods have been extensively investigated. In this study, five pairs of meroterpenoid enantiomers beyond well-known triterpenoids and polysaccharides, dayaolingzhiols I−M (1–5), were characterized from Ganoderma lucidum. Their structures were identified using spectroscopic and computational methods. Structurally, compound 1 features a novel dioxabicyclo[2.2.2]octan-3-one motif in the side chain. Ethnoknowledge-derived biological evaluation found that (+)-5 could activate Akt and AMPK phosphorylation in insulin-stimulated C2C12 cells, and (+)-5 could activate glucose uptake dose dependently in C2C12 cells. Furthermore, we found that (+)-1 (+)-4, and (–)-4 could significantly inhibit cell migration of the MDA-MB-231 cell line, of which (+)-4 showed significant inhibitory effects against cell migration of the MDA-MB-231 cell line in a dose-dependent manner. These findings revealed the meroterpenoidal composition of G. lucidum and its roles in the prevention of chronic diseases such as diabetes mellitus and triple-negative breast cancer.

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