The role of the adhesion protein tensin-3 (TNS3) in controlling basement membrane remodelling during breast cancer progression in mammalian models

Breast cancer is one of the most common cancers in women, often beginning as ductal carcinoma in situ (DCIS), where mammary epithelial cells proliferate within ducts due to the presence of the basement membrane (BM). In 30% of patients, cancer cells progress to invasive ductal carcinoma (IDC) and metastasis. The mechanisms underlying this progression remain poorly understood. Tensin 3 (TNS3), a member of the TNS family that includes TNS1, TNS2, and TNS4, interacts with β1 integrin to promote cell-ECM adhesion during this transition.
We found that TNS3 is upregulated in DCIS and IDC tumours compared to normal mammary glands in a mouse model of breast cancer. Interestingly, TNS3 downregulation in MCF10DCIS and MCF10CA1 cells suppressed invasive protrusions and reduced spheroid growth. Additionally, MCF10DCIS and MCF10CA1 cell growth on Matrigel was impaired under glutamine deprivation.
Mechanistically, downregulating β1 integrin and TNS3 significantly reduced laminin-332 expression in 3D cultured MCF10DCIS cells and impaired filopodia formation. Moreover, silencing TNS3 lowered α3 and α6 integrin levels. Blocking α3 and α6 integrin function further decreased laminin-332 expression and filopodia formation, suggesting that TNS3 modulates BM dynamics through α3 and α6 integrins. Consistently, TNS3 knockdown reduced laminin-332, α3 integrin expression, and filopodia formation in MCF10CA1 cells.
Reports suggest that TNS3 acts as a tumour promoter in cancer cells but as a tumour suppressor in non-transformed epithelial cells. Our results indicate that silencing TNS3 promotes proliferation and invasion of MCF10A cells while increasing α3 integrin, laminin-332, and filopodia formation. Overexpression of TNS3 in a Drosophila cancer model strongly impaired tumour growth and metastasis.
Overall, these findings highlight TNS3’s critical role in regulating the basement membrane and filopodia formation, acting as both a tumour promoter in cancer cells and a tumour suppressor in normal mammary epithelial cells.