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

Abstract

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer. Despite the reported interplay between tumors and tumor-associated macrophages (TAM) in fostering drug resistance and disease progression, the underlying mechanisms governing these interactions remain elusive. Here, it was found an upregulation of Collagen type V alpha 1 (COL5A1) in TNBC tissues, particularly in chemoresistant samples, correlating with an unfavorable prognosis. Functional assays demonstrated that COL5A1 played a pivotal role in fostering cancer growth, metastasis, and doxorubicin (DOX) resistance both in vitro and in vivo. In addition, the cytokine IL-6 produced by COL5A1 overexpressing TNBC cells facilitated M2 macrophage polarization. Reciprocally, TGFβ from M2 macrophages promoted TNBC DOX resistance through mediating the TGFβ/smad3/COL5A1 signaling pathway, therefore constituting a feed-back loop between TNBC cells and macrophages. Mechanistically, COL5A1 was found to interact with TGM2, inhibiting its K48-linked ubiquitination-mediated degradation. This led to an enhanced chemoresistance and increased secretion of IL-6. In summary, these findings unveiled that the upregulation of COL5A1 held significant potential in driving TNBC progression and chemoresistance by modulating macrophage polarization. This supports the proposition that targeting COL5A1 could emerge as an effective strategy against TNBC.