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January 20th, 2025
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Universidad de Buenos Aires, Facultad de Medicina, Instituto de Oncologia Angel H. Roffo, Area de Investigacion, Buenos Aires, Argentina.
cancer biology
biorxiv

SPARC is a new driver of early breast tumor progression via TGF-β -dependent mechanism.

Sciacca, M.Open in Google Scholar•Carballo, M. d. P.Open in Google Scholar•Lacunza, E.Open in Google Scholar•Marino, L.Open in Google Scholar•Cardozo, P. N.Open in Google Scholar•Rodriguez Padilla, N.Open in Google Scholar•Lopez-Lopez, T.Open in Google Scholar•Abba, M.Open in Google Scholar•Courtois, L.Open in Google Scholar•Bieche, I.Open in Google Scholaret al.

The transition of ductal carcinoma in situ (DCIS) to an invasive stage is a crucial event that involves the disruption of the basement membrane and the physical connection of the neoplastic cells with the surrounding stroma. A better understanding of the mechanisms and actors involved in progression to invasive disease will improve treatment outcomes. Membrane type 1 (MT1)-matrix metalloproteinase (MMP) has been previously identified as an essential gene involved in DCIS progression. In this work, RNA-sequencing analysis from MT1-MMPhigh cells from xenograft invasive tumors post-intraductal inoculation was used to compare against a set of human high-grade DCIS previously described. Secreted protein acidic and cysteine rich (SPARC), emerges as one of the candidate genes involved in early breast cancer progression. We found SPARC expression is up regulated in DCIS as compared to healthy breast epithelial tissues and in the invasive components of breast tumor cells relative to synchronous DCIS foci. A significant fraction of high SPARC expression cases of DCIS also exhibits high expression of MT1-MMP. In vitro, knockdown of SPARC reduced MT1-MMP expression, the degradative capacity of the cells and also the canonical activation of TGF-{beta} signalling pathway. At the mechanistic level, pharmacological inhibitors of TGFBRI decreased SPARC and MT1-MMP expression in murine and human cell lines. Furthermore, the TGFBRI inhibitors impaired the degradative capacity and 3D cell migration, which is lost in SPARC knockdown cells. In vivo, Galunisertib reduced the invasive transition of breast tumors in a new triple-negative mouse intraductal syngeneic model. Moreover, high SPARC expression was positively correlated with both, TGF-{beta} and TGFBRI 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-{beta}-dependent mechanism, suggesting TGFRI as a target for SPARC-positive patients.

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