Work

SPARC is involved in the transition from DCIS to Invasive Ductal Carcinoma via a TGFBR- Dependent Mechanism in breast cancer

Year: 2026

Type: preprint

Abstract: Background Ductal carcinoma in situ (DCIS) is a pre-invasive lesion with variable risk of progression to invasive ductal carcinoma (IDC), however, reliable predictors of invasive transition remain lacking. Membrane type I matrix metalloproteinase (MT1-MMP) is a key regulator of DCIS progression. Methods We combined RNA sequencing of MT1-MMP high and MT1-MMP low cell populations from intraductal tumor xenografts with human high-grade DCIS datasets to identify regulators of early breast cancer progression. Results Secreted Protein Acidic and Cysteine Rich (SPARC) was identified as a candidate associated with the invasive switch. SPARC was upregulated in DCIS compared to normal breast epithelium and increased in IDC, and correlated with MT1-MMP expression. Functionally, SPARC depletion reduced MT1-MMP expression, matrix degradation, and TGF-β signaling activity, while TGF-β receptor type I (TGFBRI) inhibition decreased SPARC and MT1-MMP levels, matrix degradation and cell migration. In a new triple-negative intraductal syngeneic mouse model, TGFBRI inhibition reduced the transition from in situ to invasive lesions and decreased SPARC and MT1-MMP expression. Notably, SPARC expression was not associated with metastatic dissemination, supporting a role in early progression. Conclusions Our findings identify SPARC as a TGF-β–dependent regulator of early breast cancer progression and highlight the TGFBRI–SPARC–MT1-MMP axis as a potential therapeutic target.

Source: Research Square

DOI: 10.21203/rs.3.rs-9752553/v1