scholarly journals GRP78 regulates CD44v membrane homeostasis and cell spreading in tamoxifen-resistant breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. e201900377 ◽  
Author(s):  
Chun-Chih Tseng ◽  
Ramunas Stanciauskas ◽  
Pu Zhang ◽  
Dennis Woo ◽  
Kaijin Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Surface ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Cell Spreading ◽  
Single Particle Tracking ◽  
Cell Surface Expression ◽  
Juxtamembrane Region ◽  
Tamoxifen Resistant

GRP78 conducts protein folding and quality control in the ER and shows elevated expression and cell surface translocation in advanced tumors. However, the underlying mechanisms enabling GRP78 to exert novel signaling functions at cell surface are just emerging. CD44 is a transmembrane protein and an important regulator of cancer metastasis, and isoform switch of CD44 through incorporating additional variable exons to the extracellular juxtamembrane region is frequently observed during cancer progression. Using super-resolution dual-color single-particle tracking, we report that GRP78 interacts with CD44v in plasma membrane nanodomains of breast cancer cells. We further show that targeting cell surface GRP78 by the antibodies can effectively reduce cell surface expression of CD44v and cell spreading of tamoxifen-resistant breast cancer cells. Our results uncover new functions of GRP78 as an interacting partner of CD44v and as a regulator of CD44v membrane homeostasis and cell spreading. This study also provides new insights into anti-CD44 therapy in tamoxifen-resistant breast cancer.

scholarly journals Functional inhibition of F11 receptor (F11R/junctional adhesion molecule-A/JAM-A) activity by a F11R-derived peptide in breast cancer and its microenvironment

2019 ◽  
Vol 179 (2) ◽  
pp. 325-335 ◽  
Author(s):  
Radoslaw Bednarek ◽  
Anna Selmi ◽  
Dagmara Wojkowska ◽  
Kamil Karolczak ◽  
Marcin Popielarski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endothelial Cell ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Cell Surface Expression ◽  
Microvascular Endothelial Cell

Abstract Purpose To examine the involvement of the F11R/JAM-A protein in breast cancer metastasis, we utilized the F11R/JAM-A antagonistic peptide 4D (P4D) in experiments of transendothelial migration (TEM) of breast cancer cells. Methods Experiments were conducted in the mouse 4T1 breast cancer model utilizing the human mammary epithelial cell and endothelial cell lines. The levels of soluble F11R/JAM-A (sJAM-A) in the murine plasmas were measured by ELISA. Levels of F11R/JAM-A mRNA and protein in cell lines were assessed by qRT-PCR and Western blot, respectively. Cell surface expression of F11R/JAM-A was demonstrated by flow cytometry. Functional tests included the TEM of breast cancer cells and adhesion of breast cancer cells to the endothelium. The endothelial permeability was studied by fluorescent tracer assay and by the Real-Time Cell Analysis (RTCA). Results The tumor inducers Tβ4 and TGF-β1 reduced the levels of sJAM-A in murine plasma, and reduced the F11R/JAM-A protein levels in the human microvascular endothelial cell line HMEC-1. The adhesion and TEM measured between breast cancer cells and inflamed or Tβ4-treated endothelium were inhibited by P4D. The presence of P4D did not destabilize the pre-existing tight junctions in the endothelial monolayer. The barrier-protecting effect of P4D was stronger than that of forskolin, when a booster dose of P4D was applied to the inflamed endothelium. Conclusions F11R/JAM-A protein can be considered as a novel target in the treatment of breast cancer metastasis. In vivo and clinical studies are needed to further investigate the effectiveness of F11R/JAM-A-derived peptide as a possible anti-metastatic drug.

scholarly journals Effect of HIT Components on the Development of Breast Cancer Cells

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 832
Author(s):  
Li-Yu Chen ◽  
Gurunath Apte ◽  
Annerose Lindenbauer ◽  
Marion Frant ◽  
Thi-Huong Nguyen
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Laser Scanning ◽  
Cancer Metastasis ◽  
Cell Spreading ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Platelet Factor

Cancer cells circulating in blood vessels activate platelets, forming a cancer cell encircling platelet cloak which facilitates cancer metastasis. Heparin (H) is frequently used as an anticoagulant in cancer patients but up to 5% of patients have a side effect, heparin-induced thrombocytopenia (HIT) that can be life-threatening. HIT is developed due to a complex interaction among multiple components including heparin, platelet factor 4 (PF4), HIT antibodies, and platelets. However, available information regarding the effect of HIT components on cancers is limited. Here, we investigated the effect of these materials on the mechanical property of breast cancer cells using atomic force microscopy (AFM) while cell spreading was quantified by confocal laser scanning microscopy (CLSM), and cell proliferation rate was determined. Over time, we found a clear effect of each component on cell elasticity and cell spreading. In the absence of platelets, HIT antibodies inhibited cell proliferation but they promoted cell proliferation in the presence of platelets. Our results indicate that HIT complexes influenced the development of breast cancer cells.

scholarly journals SUSD2 Proteolytic Cleavage Requires the GDPH Sequence and Inter-Fragment Disulfide Bonds for Surface Presentation of Galectin-1 on Breast Cancer Cells

2019 ◽  
Vol 20 (15) ◽  
pp. 3814 ◽  
Author(s):  
Mitch E. Patrick ◽  
Kristi A. Egland
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Cell Surface ◽  
Cancer Cells ◽  
Serine Protease ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Transmembrane Protein ◽  
Dependent Manner ◽  
Tumor Immune Evasion

Galectin-1 (Gal-1) is a 14 kDa protein that has been well characterized for promoting cancer metastasis and tumor immune evasion. By localizing to the cancer cell surface, Gal-1 induces T cell apoptosis through binding T cell surface receptors. The transmembrane protein, Sushi Domain Containing 2 (SUSD2), has been previously shown to be required for Gal-1 surface presentation in breast cancer cells. Western immunoblot analysis revealed that SUSD2 is cleaved into two fragments. However, the significance of this cleavage for Gal-1 surface localization has not been investigated. To define the location of cleavage, a mutagenesis analysis of SUSD2 was performed. Our studies demonstrated that SUSD2 is cleaved at its glycine-aspartic acid-proline-histidine (GDPH) amino acid sequence. Generation of a noncleavable SUSD2 mutant (GDPH∆-SUSD2) showed that SUSD2 cleavage was required for SUSD2 and Gal-1 plasma membrane localization. Noncleavable cysteine mutants were also unable to present Gal-1 at the cell surface, further demonstrating that SUSD2 cleavage is required for Gal-1 surface presentation. Treatment with the serine protease inhibitor, Pefabloc SC, inhibited SUSD2 cleavage in a dose dependent manner, suggesting that SUSD2 is cleaved by a serine protease. Therefore, identification and inhibition of this protease may provide a new therapeutic tool for inhibiting SUSD2 and Gal-1′s combined tumorigenic function in breast cancer.

scholarly journals Biomechanical regulation of breast cancer metastasis and progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adrianne Spencer ◽  
Andrew D. Sligar ◽  
Daniel Chavarria ◽  
Jason Lee ◽  
Darshil Choksi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Mechanical Load ◽  
Breast Cancer Metastasis ◽  
Proliferation And Metastasis ◽  
Xenograft Models ◽  
Chemotherapeutic Treatment ◽  
Complex Signaling

AbstractPhysical activity has been consistently linked to decreased incidence of breast cancer and a substantial increase in the length of survival of patients with breast cancer. However, the understanding of how applied physical forces directly regulate breast cancer remains limited. We investigated the role of mechanical forces in altering the chemoresistance, proliferation and metastasis of breast cancer cells. We found that applied mechanical tension can dramatically alter gene expression in breast cancer cells, leading to decreased proliferation, increased resistance to chemotherapeutic treatment and enhanced adhesion to inflamed endothelial cells and collagen I under fluidic shear stress. A mechanistic analysis of the pathways involved in these effects supported a complex signaling network that included Abl1, Lck, Jak2 and PI3K to regulate pro-survival signaling and enhancement of adhesion under flow. Studies using mouse xenograft models demonstrated reduced proliferation of breast cancer cells with orthotopic implantation and increased metastasis to the skull when the cancer cells were treated with mechanical load. Using high throughput mechanobiological screens we identified pathways that could be targeted to reduce the effects of load on metastasis and found that the effects of mechanical load on bone colonization could be reduced through treatment with a PI3Kγ inhibitor.

scholarly journals Differential effect of EGFR inhibitors on tamoxifen-resistant breast cancer cells

2015 ◽  
Vol 34 (3) ◽  
pp. 1613-1619 ◽  
Author(s):  
SANGMIN KIM ◽  
JEONGMIN LEE ◽  
SOO JIN OH ◽  
SEOK JIN NAM ◽  
JEONG EON LEE
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Differential Effect ◽  
Breast Cancer Cells ◽  
Egfr Inhibitors ◽  
Tamoxifen Resistant
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