Ductal carcinoma in situ (DCIS) is a proliferation of cells confined in the breast ductal-lobular unit. Currently, DCIS could be a precursor of invasive ductal carcinoma (IDC), but predicting this transition remains challenging. Previously, we have shown that MT1-MMP was essential for early breast progression using an intraductal xenograft model. In this work, RNAseq analysis from MT1-MMPhigh cells from invasive tumors post-intraductal inoculation was compared against a set of human high-grade DCIS previously described. SPARC emerges as one of the candidate genes involved in early breast cancer progression. By IHC, we observed an over-expression of SPARC in neoplastic cell compared normal tissue from 2 different cohort of patients with IDC and DCIS foci (PICBIM n=116 and Roffo n=58). SPARC expression was higher in IDC than DCIS foci (p<0,0001) and correlated with MT1-MMP levels. SPARC-positive tumors were higher in high-grade and TNBC IDC tumors (p=0,02). In a metastatic cohort of patients (n=57), lymph node metastases did not express SPARC. In the murine cell LM38-LP, MT1-MMP mRNA level and degradative capacity were reduced in KO SPARC cells (p<0,05). STRING analysis showed a medium interaction score between SPARC and TGF-B1. LM38-LP cells were sensitive to TGF-B1 pathway regulation (p<0,05; p<0,001) and KO SPARC LM38-LP cells reduced pSMAD 2/3 (p=0,003). SB431542 (20ng/ml) decreased SPARC and MT1-MMP expression in LM38-LP and human MCF10DCIS.com cells lines (p<0,001). TGF-B1 (2ng/ml) increased the degradative capacity of LM38-LP whereas, SB431542 and Galunisertib (1µg/ml), reduced it (p<0,001; p<0,05). On migration assays, we observed that the inhibitory effect of SB431542 was lost in KO SPARC cells (p<0,0001). In vivo, Galunisertib (50mg/kg) reduced the proportion and tumor area of IDC (p= 0,04). These results reveal that SPARC is involved in early tumor progression via the TGF-β1-dependent mechanism, suggesting TGFRI as a target for SPARC-positive patients.