Galectins are members of a family of ␤-galactosidesbinding proteins that have recently emerged as novel modulators in different aspects of cancer. The expression of galectins in tumors and/or the tissue surrounding them has been well documented. Since galectin-7 expression has been associated with epithelial tissues and varies significantly in various types of cancer, we have investigated for the first time its role in breast cancer. Using two preclinical mouse models, high levels of galectin-7 expression in breast cancer cells drastically increased their ability to metastasize to lungs and bones. Significant increases in the number of pulmonary metastases and osteolytic lesions were induced by overexpression of galectin-7 compared with control cells. In human tissues, galectin-7 was specifically found in myoepithelial cells of normal human breast tissue, but not in luminal cells. Its expression was severely altered in breast carcinoma, many samples showing greater than 70% of galectin-7 positive cells. High expression levels of galectin-7 were restricted to high-grade breast carcinomas, including HER2 overexpressing and basal-like groups. In HER2 overexpressing cases, galectin-7 expression was associated with lymph node axillary metastasis. Taken together, our results indicate that galectin-7 may represent a potential target for both specific detection and therapeutic inhibition of metastatic breast cancer.

Galectin-7 is found mainly in stratified squamous epithelia as well as in various other types of cancer cells. As with other members of the galectin family, the expression of galectin-7 has been shown to negatively regulate the development of some tumors while correlating with the progression of other tumor types. For example, up-regulation of galectin-7 is associated with rat mammary carcinomas and with progression to T-cell malignancy. Here, we provide evidence indicating that galectin-7 functions as an important molecule in the dissemination of lymphoma cells in vivo. We found that stable transfection of lymphoma cells with a plasmid encoding antisense galectin-7 cDNA significantly inhibited the dissemination and invasion of lymphoma cells to peripheral organs, thereby increasing the survival of mice. We also found that inhibition of galectin-7 in aggressive lymphoma cells correlated with a decreased invasion of tumor cells in target organs and a reduced expression of matrix metalloproteinase-9, a gene associated with a poor prognosis in non-Hodgkin's lymphoma. We finally examined the expression of galectin-7 in 50 specimens of different mature B-cell neoplasms and found high galectin-7 expression levels in a significant proportion of mature B-cell neoplasms but not in normal B cells. Taken together, these findings suggest that galectin-7 is a potential therapeutic target in the treatment of lymphoid malignancies.

IntroductionRecent evidence has reinforced the notion that the tumor microenvironment plays a key role in the growth and survival of hematologic malignancies. [1][2][3] In this tumor microenvironment, cancer cells are surrounded by numerous cell types including endothelial cells (ECs) of the blood and lymphatic circulation, stromal fibroblasts and a variety of bone marrow-derived cells. 4 Stromal cells express a wide variety of chemokine and growth factor receptors, rendering them responsive to the local production of soluble mediators, most notably during close contact with lymphoma cells. Interactions of tumor cells with these stromal elements are believed to be critical in the initiation and progression of the oncologic process. 5,6 For example, we have previously shown that close contact between lymphoma cells and ECs leads to the expression of several matrix metalloproteinases (MMPs), including MMP-9. 7-9 Proteolytic remodeling of extracellular matrix in tumor progression by hostderived MMP-9 has also been observed both in vivo and in vitro in human and experimental models of cancers. [10][11][12][13][14] While absence of MMP-9 does not prevent development of thymic lymphoma, 15 abnormally high levels of MMP-9 has been shown to accelerate the growth of thymic lymphoma. 14 However, while a large number of studies have focused on the molecular mechanisms that control the induction of MMPs in stromal cells, [16][17][18][19][20] the nature of the signals that suppress MMP-9 secretion in peritumoral cells remains largely unknown.The early growth response protein 1 (EGR-1) is a member of the immediate early gene family of transcription factors containing a DNA-binding domain consisting of 3 zinc fingers that regulates transcription through guanine-cystosine-rich, cis-acting promoter elements. 21,22 EGR-1 controls the expression of a wide variety of genes, many of which play a pivotal role in the regulation of cell growth, differentiation, and apoptosis. 23 However, although several studies have shown that EGR-1 promotes cancer progression [23][24][25] there is increasing evidence that EGR-1 may also exert tumor suppression. [26][27][28][29][30] In leukemia, for instance, EGR-1 has been implicated in the apoptosis of myeloma cells via its interaction with c-JUN while it behaves as a tumor suppressor against the oncogenes E2F-1 and c-MYC. [31][32][33] In the present study, we found that EGR-1 gene expression is induced in stromal cells upon close contact with lymphoma cells, an effect that is mediated by the epidermal growth factor (EGF). Using in vivo and in vitro experimental models, we further found that de novo expression of EGR-1 induced by EGF inhibits the expression of MMP-9 and decreases the growth of thymic lymphoma. Methods MiceBreeder pairs for the C57BL/6 mouse colony were purchased from The Jackson Laboratory. The proMMP9-Luc transgenic mice containing MMP-9 promoter-driven luciferase transgene in its genome were generated in the 129 background by standard microinjection techniques. Transgenic founders...