Metastasis, the epitome of cancer progression, is a pathophysical process of profound significance, because much of the lethality is from malignant neoplasms. Carbohydrate-mediated recognition leads to the formation of multi-cell emboli in the circulation, a process directly related to the development of metastases. The role of galectin-3 in the process is now established through the efforts of this continued research. Galectin-3 is a chimeric gene product with monomer subunit of ~30,000 daltons, and is an unusual protein, in that it is localized and functions in the cytoplasm, cell membrane, nucleus and the extracellular millieu. Galectin-3 is an antiapoptotic molecule that contains the NWGR anti-death motif of the bcl-2 family members and is a novel binding partner of B-catenin. The results shown here indicate that galectin-3 regulates, in part, the intersection between cell-cell adhesion and signaling during cancer progression and metastasis. It has distinct functions and recognition sites involving different cell lineages at different developmental and pathological stages including cell growth, apoptosis-resistance, adhesion, differentiation, inflammation, transformation, angiogenesis, invasion and metastasis. We now propose to define in greater detail the structural-functional relationship of galectin-3 as it relates to cellular localization, cell growth, apoptosisresistance, cell-cell recognition, angiogenesis, tumor growth and hematogenous spread of tumor cells. To this end we propose the following: 1) Determine the pathway for shuttling gal-3 between the cytoplasm and nucleus and its effect on tumor progression and metastasis. 2) Delineate the molecular role of gal-3 in Wnt signaling pathway during breast cancer progression and the impact of pathway inhibitors on breast cancer tumor growth and metastasis. 3) a) Establish the functional role of cleaved gal-3 in angiogenesis, invasion and metastasis, using cellular and genetic approaches both in vitro and in vivo, and b) Explore the feasibility of utilizing differential anti-gal-3 antibodies (specifically recognizing intact versus cleaved gal-3) as as possible surrogate prognostic/diagnostic marker for MMPs activity in human cancers. It is expected that the results obtained from this study will provide a better understanding of galectin-3 and its interacting ligands in tumor progression and metastasis and will further the developments of specific reagents for the detection and interventions in these processes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Woodhouse, Elizabeth
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Wayne State University
Schools of Medicine
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Nakajima, Kosei; Kho, Dhong Hyo; Yanagawa, Takashi et al. (2016) Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis. Cancer Res 76:1391-402
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Nangia-Makker, Pratima; Raz, Tirza; Tait, Larry et al. (2013) Ocimum gratissimum retards breast cancer growth and progression and is a natural inhibitor of matrix metalloproteases. Cancer Biol Ther 14:417-27

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