Abstract 107: Galectin-1 plays a critical role in normal and neoplastic mammary gland morphogenesis and metastatic spreading in breast cancer

Abstract Galectins are a family of glycan-binding proteins that regulate neoplastic transformation, angiogenesis, cell adhesion and tumor-immune escape. Galectin-1 (Gal-1), a prototype member of this family, binds to multiple N-acetyllactosamine units in N- and O-glycans on cell surface glycoproteins. Biologically, Gal-1 plays a key role in the creation of an immunosuppressed tumor microenvironment (TME) by acting as a negative regulator of the immune response, fostering tumor immune-escape, stimulating an invasive, stem-like phenotype and enhancing metastasis in several tumors. In this work we focus on the relevance of the Gal-1-glycan axis in the TME, metastatic progression and antitumor immune response, and we aim to address the role that Gal-1 plays in normal and transformed mammary gland development. First, we observed that C57BL/6 female mice deficient for Gal-1 (Lgals1-/- KO) have an impaired mammary branch morphogenesis in response to progesterone stimulus as compared to their C57BL/6 WT counterparts. To tackle the mechanism underlying this deficiency in mammary branching, we performed cell sorting based on surface markers (EpCAM and CD49f)to categorize the isolated mammary cells from C57BL/6 WT and C57BL/6 Lgals1-/- KO mice into four main populations: luminal (EpCAMhigh-CD49flow), basal (EpCAMlow-CD49fmed), stromal (EpCAMneg-CD49fneg), and mammary stem cells (MaSC) (EpCAMlow-CD49fhigh). Each population’s purity was evaluated by Real Time PCR (qPCR) using specific markers (PR, ER, Vim, a-SMA, Nanog) and we observed that Lgals1-/- KO mice present a decreased percentage of luminal and MaSC cells (Spectral CyTEK) in comparison to the Gal-1 sufficient strain, which may contribute to the reduced branching. To then analyze the role of Gal-1 in mammary tumorigenesis and metastasis, we developed a MMTV-PyMT transgenic mouse model WT or KO for Gal-1 (lgals1-/-).Using this novel experimental model, we observed that that PyMT-Gal1-KO mice present a delay in tumor burden and a longer tumor-free survival time, with an overall lower number of transformed ducts in the mammary gland and reduced lung metastasis, alongside a reduced mammary gland branching morphogenesis. Our findings highlight the relevance of Gal-1 in regulating normal mammary gland morphogenesis and assert its critical role in metastatic spreading in breast cancer. From a therapeutical point of view, Gal-1 can be considered as a promising target in metastatic breast cancer. Citation Format: Magali Berton, Ramiro Perrotta, Tomás Dalotto-Moreno, Mahmoud D. Yamil, Sabrina Gatto, Rosa Morales, Gabriel A. Rabinovich, Mariana Salatino. Galectin-1 plays a critical role in normal and neoplastic mammary gland morphogenesis and metastatic spreading in 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 107.