Extradomain-B Fibronectin is a molecular marker of invasive breast cancer cells

Abstract

invasiveness 28 Abbreviations 29 BCa -Breast cancer 30 EDB-FN -Extradomain-B fibronectin 31 FN1 -Fibronectin 32 MRI -Magnetic resonance imaging 33 PET -Positron-emission tomography 34 CT -Computed tomography 35 TME -Tumor microenvironment 36 ECM -Extracellular matrix 37 TGF-β -Transforming growth factor-β 38 EMT -Epithelial to mesenchymal transition 39 CEA -Carcinoembryonic antigen 40 41 42 43 44 45 46 47 48 49 50 51 Summary Statement 52 Dynamic changes in invasive properties of breast cancer cells directly influence extradomain-B 53 fibronectin levels, suggesting its potential role as a molecular marker for active surveillance and 54 therapeutic monitoring of breast cancer. 55 Abstract 56Breast tumor heterogeneity is a major impediment to oncotherapy. Tumor cells undergo rapid 57 clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of 58 specific markers of these high-risk tumors precludes efficient therapeutic and diagnostic 59 management of breast cancer. Given the critical function of tumor microenvironment in the 60 oncogenic circuitry, we sought to determine the role of the extracellular matrix oncoprotein, 61 extradomain-B fibronectin (EDB-FN), as a molecular marker of aggressive cancers. High-risk 62 invasive cell lines generated from relatively less invasive MCF7 and MDA-MB-468 breast cancer 63 cells by long-term TGF-β treatment and chemoresistance demonstrated hybrid epithelial-64 mesenchymal phenotype, enhanced motility, and significantly elevated EDB-FN levels in 2D-and 65 3D-cultures. To determine if EDB-FN could serve as a therapy-predictive marker, the invasive cell 66 lines were treated with MK2206-HCl, a pan-AKT inhibitor. Phospho-AKT depletion reduced 67 EMT and invasion of the populations, with a concomitant decrease in EDB-FN expression, partly 68 through the phosphoAKT-SRp55 pathway, demonstrating that EDB-FN expression is strongly 69 associated with high-risk breast cancer. EDB-FN is a promising molecular marker for accurate 70 detection, differential diagnosis, and non-invasive therapeutic surveillance of aggressive breast 71 cancer. 72 73 74 75 76 77 78 79Breast cancer (BCa) is a devastating disease that accounts for 41,000 deaths each year in 80 the US (Siegel et al., 2018). Although the survival rate for patients with localized BCa is close to 81 99%, it declines precipitously in patients with distant metastases and drug resistance (Siegel et al., 82 2018, DeSantis et al., 2017). A major stumbling block in the clinical management of the disease 83 is tumor heterogeneity, which plays a role in the dynamic nature of BCa progression (Baird and 84 Caldas, 2013). Whole genome sequencing and profiling studies have demonstrated that breast 85 tumors of the same histological subtype exhibit distinct molecular portraits and discrete trajectories 86 in individual BCa patients at different stages (Tsang and Tse, 2019, Eliyatkin et al., 2015, Baird 87 and Caldas, 2013). Stochastic mutations, genome instability, and clonal evolution arising from 88 selective pre...

Effective MR Molecular Imaging of Triple Negative Breast Cancer With an EDB-Fibronectin-Specific Contrast Agent at Reduced Doses

“…EDB-FN is overexpressed in poorly differentiated, triple negative breast cancer. (A) Endogenous EDB-FN mRNA levels is significantly elevated in triple negative breast cancer cell lines MDA-MB-231 and Hs578T (claudin-low ER − , PR − , HER2 − ) compared to MCF7 (luminal A; ER + , PR +/− , HER2 − ) [** p < 0.01, (22)]. mRNA was normalized to 18S mRNA control.…”