Bcl3 Selectively Promotes Metastasis of ERBB2-Driven Mammary Tumors

Abstract

Bcl3 is a putative proto-oncogene deregulated in hematopoietic and solid tumors. Studies in cell lines suggest that its oncogenic effects are mediated through the induction of proliferation and inhibition of cell death, yet its role in endogenous solid tumors has not been established. Here, we address the oncogenic effect of Bcl3 in vivo and describe how this Stat3-responsive oncogene promotes metastasis of ErbB2-positive mammary tumors without affecting primary tumor growth or normal mammary function. Deletion of the Bcl3 gene in ErbB2-positive (MMTV-Neu) mice resulted in a 75% reduction in metastatic tumor burden in the lungs with a 3.6-fold decrease in cell turnover index in these secondary lesions with no significant effect on primary mammary tumor growth, cyclin D1 levels, or caspase-3 activity. Direct inhibition of Bcl3 by siRNA in a transplantation model of an Erbb2-positive mammary tumor cell line confirmed the effect of Bcl3 in malignancy, suggesting that the effect of Bcl3 was intrinsic to the tumor cells. Bcl3 knockdown resulted in a 61% decrease in tumor cell motility and a concomitant increase in the cell migration inhibitors Nme1, Nme2, and Nme3, the GDP dissociation inhibitor Arhgdib, and the metalloprotease inhibitors Timp1 and Timp2. Independent knockdown of Nme1, Nme2, and Arhgdib partially rescued the Bcl3 motility phenotype. These results indicate for the first time a cell-autonomous disease-modifying role for Bcl3 in vivo, affecting metastatic disease progression rather than primary tumor growth. Cancer Res; 73(2); 745-55. Ó2012 AACR.

Variant of BCL3 gene is strongly associated with five-year survival of non-small-cell lung cancer patients

“…The immunohistochemical analysis of BCL3 protein revealed statistically significant higher expression levels in neoplastic tissues compared to tumor-adjacent, normal lung specimens where no signal was detected. This finding is consistent with published data reporting deregulation of BCL3 expression in other solid tumors such as breast cancer [12][13][14][15], prostate cancer [16], nasopharygeal carcinomas [17], endometrial tumors [18] and colorectal cancer [19]. The overexpression of BCL3 in all histological subtypes and all stages of NSCLC may reflect the decisive role that this molecule plays in lung carcinogenesis and tumor progression.…”

“…In addition, BCL3 has been documented to be deregulated in a number of solid tumors including breast cancer [12][13][14][15], prostate cancer [16], nasopharygeal carcinomas [17], endometrial tumors [18] and colorectal cancer [19].…”

The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis

“…A growing number of studies have been reported using the NIC mice and none have observed haplo-insufficiency for genes required for Neu-induced mammary tumorigenesis. Genes examined for their role in ERBB2-mediated mammary tumorigenesis include ShcA [32], β-catenin [42], Bcl3 [43], hexokinase II [44], DOCK1 [45], LKB1 [46], 14-3-3σ [47], STAT1 [48], and specific isoforms of phosphatidylinositol 3’-kinase [49]. The haplo-insufficiency observed in our study indicates a strong requirement for GLUT1 and glucose in mammary tumorigenesis.…”

Bcl3 regulates pro-survival and pro-inflammatory gene expression in cutaneous T-cell lymphoma

“…Elevated Bcl3 expression results in increased cell proliferation, survival and malignant potential. Studies have demonstrated increased Bcl3 expression in the different types of hematopoietic and solid cancers [44–49], yet its function and regulation in CTCL have not been investigated.…”