Expression of Galectin-7 Is Induced in Breast Cancer Cells by Mutant p53

Abstract

Galectin-7 was initially described as a marker of epithelial differentiation expressed in the stratified epithelium of various tissues. Like other members of the galectin family, its expression level is often significantly altered in cancer cells. In breast cancer, its expression is significantly augmented in aggressive molecular subtypes, most notably in estrogen receptor-negative tumors and in cell lines with a basal-like phenotype. Studies using experimental mouse models have further shown high expression of galectin-7 was sufficient to increase the metastatic behavior of poorly metastatic breast cancer cells, rendering them more resistant to apoptosis. This expression pattern in breast cancer cells is unexpected because galectin-7 was originally identified as a p53-induced gene. To address this paradox, we have examined the molecular mechanisms regulating galectin-7 in breast cancer cells. Our results showed that transfection of breast cancer cells with expression vectors encoding mutant p53 was sufficient to induce galectin-7 at both mRNA and protein levels. Doxorubicin treatment of breast cancer cells harboring a mutant p53 also induced galectin-7. This induction was specific since knockdown of endogenous mutant p53 inhibited doxorubicin-induced galectin-7 expression. The p53-induced galectin-7 expression in breast cancer cells correlated with increased NF-κB activity and was inhibited by NF-κB inhibitors, indicating that the ability of mutant p53 to induce galectin-7 was dependent on NF-κB activity. The implication of NF-κB was further supported by data showing that NF-κB bound to the endogenous galectin-7 promoter and that TNFα-induced galectin-7 expression was abolished by NF-κB inhibitors. Taken together, our data provide an explanation to the observed high galectin-7 expression levels in cancer cells and suggest that galectin-7 could be part of a common pathway used by mutant p53 to promote cancer progression.

The CCAAT/Enhancer-Binding Protein Beta-2 Isoform (CEBPβ-2) Upregulates Galectin-7 Expression in Human Breast Cancer Cells

“…The ability of C/EBPβ to displace NF-κB on the galectin-7 promoter was confirmed by ChIP analysis which showed that while endogenous p50 is constitutively bound to the galectin-7 promoter, transfection of C/EBPβ-2 displaced the p50 homodimers, leading to a strong activation of galectin-7 expression. However, in presence of transcriptionally active NF-κB complexes, containing c-Rel for example, NF-κB could possibly exert a positive influence of galectin-7 expression, as we recently showed [38]. In other words, galectin-7 expression in cancer cells with an inactive p53 pathway possibly involves C/EBP and/or NF-κB.…”

Towards molecular mechanisms regulating the expression of galectins in cancer cells under microenvironmental stress conditions

“…Since both p53 and NF-jB belong to stress-induced transcription factors, the corresponding upregulation of galectin-7 should be considered in the context of specific cellular stress responses with differential outcomes, which fits perfectly with the conceptual paradigm of stress-induced selection between cell death or cell survival. Indeed, the biological role of galectin-7 cannot be solely related to its pro-apoptotic functions due to the crosstalk between both p53 and NF-jB, as recently demonstrated in MCF7 breast cancer cells [65]. In addition, recent studies have revealed that the upregulation of galectin-7 in breast cancer cell lines MCF7 and MDA-MB-231 is driven by C/EBPb-2, which can explain the paradox of concomitant galectin-7 overexpression in cancer cells and p53 mutation [66].…”

TP53 Mutants in the Tower of Babel of Cancer Progression

“…The target genes of TP53 mutant/TFs complexes are quite diverse in terms of their biological effects comprising genes that stimulate proliferation, inhibit apoptosis, promote chemoresistance, and influence EMT transition [Brosh and Rotter, ; Liu et al., ; Kogan‐Sakin et al., ; Freed‐Pastor and Prives, and reference therein; Kalo et al., ; Noll et al., ; Vaughan et al., ; Campion et al., ; Garritano et al., ]. These genes include, among others, c‐MYC [Frazier et al., ], PCNA (Proliferating Cell Nuclear Antigen), hTERT (human Telomerase Reverse Transcriptase)[Scian et al., ], ASNS (Asparagine Synthetase) [Scian et al., ], EGFR , EGR1 (Early Growth Response 1) [Weisz et al., ], and ABCB1 (Multi Drug Resistance‐1), the first gene discovered as TP53 mutant target [Chin et al., ].…”