Loss of MXRA8 Delays Mammary Tumor Development and Impairs Metastasis
Kaitlyn E Simpson1, Christina A Staikos1, Katrina L Watson1
1Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.
Abstract:
Matrix-remodeling-associated protein 8 or MXRA8 is a transmembrane protein that can bind arthritogenic alpha viruses like the Chikungunya virus and provide viral entry into cells. MXRA8 can also interact with integrin β3 and thus possibly regulate cell-cell interactions and binding to the extracellular matrix. While MXRA8 has been associated with reduced survival in patients with colorectal and renal clear cell cancers, the role of MXRA8 in breast cancer remains largely unexplored. Therefore, the aim of this research was to determine the role of MXRA8 in breast cancer by knocking out MXRA8 in the human triple-negative breast cancer cell line MDA-MB-231. The loss of MXRA8 reduced cell proliferation in vitro but had no effect on apoptosis or migration in cultured cells. However, the loss of MXRA8 significantly delayed tumor development and reduced metastatic dissemination to the lungs in a xenograft model. RNA sequencing identified three genes, ADMATS1, TIE1, and BMP2, whose expression were significantly reduced in MXRA8-knockout tumors compared to control tumors. MXRA8 staining of a human breast cancer tissue array revealed higher levels of MXRA8 in primary tumors and metastases of aggressive tumor subtypes (TNBC and HER2+) compared to less aggressive, ER+ breast cancers. Our findings demonstrate for the first time that MXRA8 regulates the progression of human TNBC possibly through influencing the interaction of tumor cells with their microenvironment.
Insights
Matrix-remodeling-associated protein 8 (MXRA8) regulates breast cancer progression. Loss of MXRA8 reduced tumor growth and metastasis in models, suggesting MXRA8 as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- Matrix-remodeling-associated protein 8 (MXRA8) is a transmembrane protein involved in viral entry and cell interactions.
- Previous studies linked MXRA8 to survival in other cancers, but its role in breast cancer was unknown.
Purpose of the Study:
- To investigate the role of MXRA8 in human breast cancer progression.
- To determine the effect of MXRA8 loss on triple-negative breast cancer (TNBC) cell behavior and tumor development.
Main Methods:
- MXRA8 was knocked out in the MDA-MB-231 human triple-negative breast cancer cell line.
- Cell proliferation, apoptosis, and migration were assessed in vitro.
- Tumor development and lung metastasis were evaluated in a xenograft mouse model.
- RNA sequencing was performed on tumors, and MXRA8 expression was analyzed in human breast cancer tissues.
Main Results:
- Loss of MXRA8 reduced cell proliferation in vitro but did not affect apoptosis or migration.
- MXRA8 knockout significantly delayed tumor growth and reduced lung metastasis in vivo.
- Expression of ADMATS1, TIE1, and BMP2 was decreased in MXRA8-knockout tumors.
- Higher MXRA8 levels were found in aggressive breast cancer subtypes (TNBC, HER2+) and metastases.
Conclusions:
- MXRA8 plays a significant role in the progression and metastasis of human triple-negative breast cancer.
- MXRA8 may influence tumor progression by affecting interactions between tumor cells and their microenvironment.
- MXRA8 is a potential biomarker for aggressive breast cancer subtypes and a possible therapeutic target.
