Abstract 718: The crucial role of SPARC during the transition from in situ to invasive breast cancer

Breast carcinomas are classified as ductal carcinoma in situ (DCIS) or invasive carcinoma (IDC) depending on the degree of invasion. DCIS is generally found adjacent to IDC in the primary tumor and is considered a precursor of IDC. Still, it has not been possible to identify features that predict the progression to more advanced stages. We have previously demonstrated that MT1-MMP, a key membrane-associated metalloprotease (MMP), involved in the cleavage of the extracellular matrix is essential for the transition from in situ to invasive tumors using intraductal xenograft model (Lodillinsky, 2016; 2021). 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 (Abba, 2015). Secreted protein acidic and cysteine-rich (SPARC) emerges as a candidate gene in early breast cancer progression. By IHC, we observed an over-expression of SPARC in neoplastic cells compared to normal tissue from 2 different cohorts of patients with IDC and DCIS foci (PICBIM n=55 and Roffo n=34). In matched samples, SPARC levels were higher in IDC than DCIS tumors (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, suggesting its specific role in early breast cancer progression. 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 cell 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) in a new mouse intraductal syngeneic model. Moreover, high SPARC expression was positively correlated with both, TGF-β and TGFBR1 in a basal type of breast cancer collection supporting our findings. This study identifies SPARC as a driver of early tumor progression via a TGF-B1-dependent mechanism, suggesting TGFRI as a target for SPARC-positive patients. Citation Format: Marianela Sciacca,Marcela S. Villaverde,María del Pilar Carballo,Ezequiel Lacunza,Lina Marino,Noelia Paola Cardozo,Naira Rodríguez Padilla,Martin Abba, Érica Rojas Bilbao,Pablo J Sáez,Ana María Eiján,Catalina Lodillinsky. The crucial role of SPARC during the transition from in situ to invasive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 718.