SARS-CoV-2 M Protein induce the proliferation and transformation of Breast Cancer Cells


The researchers of Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba, Tsukuba, Japan have investigated the impact of SARS-CoV-2 proteins on breast cancer cells (BCC).

The results suggested that SARS-CoV-2 M protein induced the mobility, proliferation, stemness and in vivo metastasis of a triple-negative breast cancer (TNBC) cell line, MDA-MB-231, which are involved in the upregulation of NFκB and STAT3 pathways. 

Therefore, SARS-CoV-2 infection might promote the ability of aggressive BCC to induce the malignant phenotypes of the other non-aggressive BCC.

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Numerous studies have suggested that, in addition to having a high risk of SARS-CoV-2 infection, cancer patients might have an increased risk of accelerated cancer progression following infection (6–10). In addition, several case reports showed that breast cancer developed worsened outcomes after being infected by SARS-CoV-2, including new metastases and death due to tumor progression (8, 9).

In the present study, our results demonstrated that SARS-CoV-2 M protein stimulated the migration, invasion and expression of EMT genes in both MDA-MB-231 cells, a TNBC cell line, and MCF-7 cells, a hormone-dependent BCC line (28, 29). These results were in line with those of a previous study in which sera from COVID-19 patients induced EMT and Vimentin, Zeb1 and Snail expression in lung, breast and colon cancer cells in vitro (10).

Previous study suggested that breast tumor tissues from TNBC patients showed the expression of ACE2, a receptor of SARS-CoV-2 (30). In the present study, we found that while MCF-7 cells showed the low expression of ACE2 and TMPRSS2 on the cell membrane surfaces, MDA-MD-231 cells exhibited the high expression of these receptors (Supplementary Figure 1).

Among subtypes of breast cancer, TNBC is an aggressive type with a poor prognosis and low efficacy of targeted treatment (31). This raises concerns that cancer progression might be exacerbated when TNBC patients are infected with SARS-CoV-2. Of note, our finding suggested that MDA-MB-231 cells, but not MCF-7 cells, showed the induced aggressive phenotypes, including proliferation, stemness and in vivo metastasis by M protein. Therefore, it is necessary to perform further studies with a long-term follow-up of TNBC patients after SARS-CoV-2 infection.

In BCC, the activation of NFκB, a proinflammatory transcription factor, drives the inflammatory responses, proliferation, migration and invasion, leading to cancer development and progression. NFκB is also involved in the expansion of breast cancer stem cells, which are intimately associated with cancer relapse and metastasis.

In clinical studies, the enhanced activation of NFκB is associated with the breast tumor size, malignant progression, aggressive behavior and metastases in breast cancer (23). A previous study reported that M protein of coronaviruses triggered the NFκB signaling pathway in MDA-MB-231 cells (32). Consistently, our study showed that M protein of SARS-CoV-2 activated the NFκB pathway, which is responsible for the upregulation of EMT and tumor progression-related genes, such as Zeb1/2, Snail, Twist and HIF-1α, in MDA-MB-231 cells (33).

In addition, the activation of the NFκB pathway in M protein-treated MDA-MB-231 cells also induced the expression of inflammatory cytokines, including IL6, IL8, and TNFα, which are involved in tumor initiation and homing and metastasis of BCC (34–36) and might contribute to the amplification of the cytokine storm.

Numerous studies reported that STAT3, a signaling pathway associated with migration, invasion and cell plasticity, is associated with the NFκB pathway and stem-like phenotype of BCC (24, 37, 38). In addition, STAT3 was reported to be activated by inflammatory cytokines, such as IL6, IL8 and TNFα, which enhance breast cancer proliferation, invasion and metastasis through the upregulation of Twist, Snail, Slug, Vimentin and HIF-1α (24).

In the present study, our findings suggested crosstalk between the NFκB and Jak/STAT3 signaling pathways through the autocrine expression of IL6, IL8 and TNFα in MDA-MB-231 cells induced by SARS-CoV-2 M protein. Therefore, the NFκB and Jak/STAT3 signaling pathways might be promising targets of treatment for TNBC patients who develop COVID-19 infection.

Tumors are a heterogenous mixture of cancer cells, in which non-aggressive cells can acquire new phenotypes such as malignancy through communication with aggressive cells (25). By coculturing of MCF-7, as a non-aggressive BCC, with MDA-MB-231, as an aggressive BCC, we found that MDA-MB-231 cells induced the proliferation, migration, and the expression of Vimentin, a mesenchymal marker, of MCF-7 cells.

Our data are in line with those of previous studies which suggested that TNBC cells induce other subtypes of BCC to transform to an aggressive phenotype (39, 40). Of note, our findings suggested that M protein induction amplified the ability of MDA-MB-231 cells to induce the transition to an aggressive phenotype of MCF-7 cells, including the migration, proliferation, stemness and inflammatory cytokine expression, which were not happened in MCF-7 cells directly treated by M protein (Figure 5).

Interestingly, our findings showed that the coculture of MCF-7 cells with M protein-treated MDA-MB-231 cells significantly induced the expression of ACE2 in MCF-7 cells. As ACE2 also serves as a biomarker of EMT and metastasis (15, 41), these data hinted that the upregulation of ACE2 by M protein-induced aggresstive BCC might facilitate the infection of SARS-CoV-2 and metastasis in non-aggressive BCC; suggesting that, in the heterogenous mixture of cells inside tumors, SARS-CoV-2-infected aggressive BCC may affect non-aggressive BCC through secretome and cytokine storm and promote a poor general outcome of tumor progression.

Our present data were based on established cell lines instead of patient samples; therefore, it is worth to investigate the effects of SARS-CoV-2 infection on the interaction between aggressive BCC and non-aggressive BCC derived from breast cancer patients.

Numerous reports showed the existence of SARS-CoV-2 viral proteins in sera of COVID-19 patients (42–45), suggesting that in addition to the direct infection of SARS-CoV-2 into cells, free viral proteins of SARS-CoV-2 in sera might also affect the surrounding cells.

However, although several studies reported the effects of SARS-CoV-2 proteins on numerous types of cells (46–48), how SARS-CoV-2 protein, such as M protein, gets internalized into the cell is still obscured. Therefore, it is noteworthy for a further study to examine whether M protein binds to a specific receptor in the membrane surface of breast cancer cells or is non-selectively internalized into cells through macropinocytosis (49).


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