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COL5A1 promotes triple-negative breast cancer progression by activating tumor cell-macrophage crosstalk

Oncogene (2024)Cite this article

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Abstract

Triple-negative breast cancer (TNBC) is an exceptionally aggressive subtype of breast cancer. Despite the recognized interplay between tumors and tumor-associated macrophages in fostering drug resistance and disease progression, the precise mechanisms leading these interactions remain elusive. Our study revealed that the upregulation of collagen type V alpha 1 (COL5A1) in TNBC tissues, particularly in chemoresistant samples, was closely linked to an unfavorable prognosis. Functional assays unequivocally demonstrated that COL5A1 played a pivotal role in fueling cancer growth, metastasis, and resistance to doxorubicin, both in vitro and in vivo. Furthermore, we found that the cytokine IL-6, produced by COL5A1-overexpressing TNBC cells actively promoted M2 macrophage polarization. In turn, TGFβ from M2 macrophages drived TNBC doxorubicin resistance through the TGFβ/Smad3/COL5A1 signaling pathway, establishing a feedback loop between TNBC cells and macrophages. Mechanistically, COL5A1 interacted with TGM2, inhibiting its K48-linked ubiquitination-mediated degradation, thereby enhancing chemoresistance and increasing IL-6 secretion. In summary, our findings underscored the significant contribution of COL5A1 upregulation to TNBC progression and chemoresistance, highlighting its potential as a diagnostic and therapeutic biomarker for TNBC.

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Fig. 1: Elevated levels of COL5A1 correlated with chemoresistance and poor prognosis in TNBC.
Fig. 2: COL5A1 overexpression promoted resistance to doxorubicin of breast cancer cells.
Fig. 3: COL5A1 induced macrophage polarization toward an M2 phenotype through IL-6/JAK2/STAT3 signaling pathway.
Fig. 4: COL5A1 targeted TGM2 through suppressing TGM2 K48-ubiquitination to inhibit the proteasomal degradation.
Fig. 5: TGM2 knockdown partially reversed the promotion effect of COL5A1 overexpression in TNBC cells.
Fig. 6: COL5A1 overexpression TNBC-conditioned macrophage remarkably promoted the chemoresistance process through TGFβ in TNBC cells.
Fig. 7: Enforced expression of COL5A1 promoted the growth, doxorubicin resistance, and M2 macrophage polarization of breast cancer in vivo.

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Source data and reagents are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank TCGA,GEO and Metabric databases for providing data.

Funding

This work was supported by Special Foundation for Taishan Scholars (No. ts20190971), Foundation from Clinical Research Center of Shandong University (No. 2020SDUCRCA015), National Natural Science Foundation of China (Nos. 81902697, 82373267, and 81972475).

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Authors and Affiliations

  1. Department of Breast Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Xi Chen, Chenao Ma, Yaming Li, Yiran Liang, Tong Chen, Dianwen Han, Dan Luo, Ning Zhang & Qifeng Yang

  2. Pathology Tissue Bank, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China

    Wenjing Zhao, Lijuan Wang & Qifeng Yang

  3. Research Institute of Breast Cancer, Shandong University, Jinan, 250012, Shandong, China

    Qifeng Yang

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Contributions

QFY and XC designed the experiment; XC, CAM, YML, YRL, TC and DL performed the experiments; XC and CAM performed data analysis and prepared the figures/tables; DL, WJZ, LJW collected samples; XC, CAM and DWH wrote the paper; XC, NZ and QFY revised the paper.

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Correspondence to Qifeng Yang.

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Chen, X., Ma, C., Li, Y. et al. COL5A1 promotes triple-negative breast cancer progression by activating tumor cell-macrophage crosstalk. Oncogene (2024). https://doi.org/10.1038/s41388-024-03030-3

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