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Published on: October 27, 2020
Targeting cell surface GRP78-CD44v interaction suppresses cell migration in triple-negative breast cancer cells
Chun-Chih Tseng1,2,3, Pu Zhang4,5,6, Mari B Ishak Gabra7
1Department of Biochemistry and Molecular Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, 90089, CA, USA. charles.tseng@stjude.org.
Abstract:
Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER-2 amplification, rendering it unresponsive to endocrine and HER2-targeted therapies. GRP78 (78 kDa glucose-regulated protein), a key endoplasmic reticulum (ER)-resident chaperone involved in protein folding and stress response, has been observed atypically localized on the cell surface of various cancer and stressed cell types, where it engages in non-canonical signaling and cellular functions. Cell surface GRP78 (csGRP78) is preferentially expressed in malignant cells relative to normal tissue, making it an attractive therapeutic target. In this study, we report that over 70% of MDA-MB-231 TNBC cells express csGRP78. Interestingly, MDA-MB-231 cells predominantly exhibit a distinct unipolar morphology, with csGRP78 prominently co-localizing with the variant isoform of CD44 (CD44v, containing variable exon 3) at the anterior region of the cell. Co-localizations of csGRP78 and CD44v were also observed in MDA-MB-231 tumor xenografts, supporting its relevance in vivo. Importantly, targeting csGRP78 with the monoclonal antibody 76-E6 downregulated CD44v expression, inhibited Src kinase signaling, disrupted cell morphology, and suppressed cell motility. We further mapped the epitope of GRP78 targeted by 76-E6. Together, our findings identify csGRP78 as a functional regulator of cell morphology and migration at least in part via a csGRP78-CD44v axis and underscore its potential as a therapeutic target in TNBC.
Insights
Cell surface GRP78 (78 kDa glucose-regulated protein) is highly expressed in triple-negative breast cancer (TNBC) cells. Targeting this protein with antibody 76-E6 impacts cell shape and movement, suggesting it
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Triple-negative breast cancer (TNBC) lacks ER, PR, and HER2 targets, necessitating novel therapeutic strategies.
- Cell surface GRP78 (csGRP78), an ER chaperone, is upregulated in cancers and involved in non-canonical signaling.
- csGRP78 is a potential therapeutic target due to its preferential expression on malignant cells.
Purpose of the Study:
- To investigate the role and therapeutic potential of cell surface GRP78 (csGRP78) in triple-negative breast cancer (TNBC).
- To explore the relationship between csGRP78 and CD44 variant isoforms in TNBC cells.
- To evaluate the efficacy of targeting csGRP78 with the monoclonal antibody 76-E6.
Main Methods:
- Characterization of csGRP78 expression in MDA-MB-231 TNBC cells and xenografts.
- Immunofluorescence co-localization studies of csGRP78 and CD44v.
- Treatment of TNBC cells with anti-csGRP78 antibody 76-E6.
- Assessment of downstream signaling pathways (Src kinase) and cellular functions (morphology, motility).
Main Results:
- Over 70% of MDA-MB-231 TNBC cells express csGRP78, often co-localizing with CD44v at the cell's anterior.
- csGRP78 and CD44v co-localization was confirmed in vivo in tumor xenografts.
- Antibody 76-E6 targeting csGRP78 downregulated CD44v, inhibited Src kinase, altered cell morphology, and reduced cell motility.
- The epitope targeted by 76-E6 on GRP78 was mapped.
Conclusions:
- csGRP78 regulates TNBC cell morphology and migration, partly through a csGRP78-CD44v axis.
- csGRP78 represents a promising therapeutic target for triple-negative breast cancer.
- Targeting csGRP78 may offer a novel treatment strategy for TNBC patients.
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