Tumor necrosis factor deficiency inhibits mammary tumorigenesis and a tumor necrosis factor neutralizing antibody decreases mammary tumor growth in neu/erbB2 transgenic mice

Abstract

Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine that is synthesized and secreted by cells of the immune system, as well as by certain epithelia and stroma. Based on our previous studies demonstrating TNF-stimulated proliferation of normal and malignant mammary epithelial cells, we hypothesized that TNF might promote the growth of breast cancer in vivo. To test this, we generated bigenic mice that overexpressed activated neu/erbB2 in the mammary epithelium and whose TNF status was wild-type, heterozygous, or null. Mammary tumorigenesis was significantly decreased in TNF−/− mice (n = 30) compared with that in TNF+/+ mice (n = 27), with a palpable tumor incidence of 10.0% and 44.4%, and palpable tumors/mouse of 0.10 ± 0.06 and 0.67 ± 0.17, respectively. Tumorigenesis in the heterozygous group fell between that in the TNF +/+ and TNF−/− groups, but was not significantly different from either of the homozygous groups. The decreased tumor development in the TNF−/− mice was associated with a decreased proliferative index in the lobular and ductal mammary epithelium. To further investigate the role of TNF in breast cancer, mammary tumor-bearing mice whose tumors overexpressed wild-type neu/ erbB2 were treated with a TNF-neutralizing antibody or a control antibody for 4 weeks (n = 20/group). Mammary tumor growth was significantly inhibited in mice treated with the anti-TNF antibody compared with the control antibody. Together, these data show a stimulatory role for TNF in the growth of breast tumors and suggest that TNF antagonists may be effective in a subset of patients with breast cancer.

Oncogene-Driven Intrinsic Inflammation Induces Leukocyte Production of Tumor Necrosis Factor That Critically Contributes to Mammary Carcinogenesis

“…However, in our model, this is unlikely because NeuT-derived tumor cell lines treated with recombinant TNF neither proliferated nor underwent apoptosis, consistent with the undetectable expression of TNFRs on tumor cells (data not shown). This is in contrast with a recent report showing that erbB2 transgenic mice that were also knocked out for TNF had reduced cell growth, apparently because of the interrupted autocrine loop in which tumor produced TNF fuelled cell proliferation (25). Although in the presence of a similar reduction in tumor progression, TNF knockdown from embryonic life or from adulthood underscores major differences including the possible activation of compensatory mechanisms in the former versus the prompt withdrawal at different stages of tumor progression, dosing the time of BMT, in the latter case.…”

“…This treatment prevented tumor growth as long as the antibody was administered, a finding in line with the results of other studies (25). Because BMT with TNF KO donors permanently removed leukocyte-produced TNF, the antibody treatment would require continuous administration to be equally effective.…”

“…Expression of TNF and its receptors has been shown in benign and malignant human breast tissues (24), but its role in mammary carcinogenesis and its involvement in the intrinsic inflammatory pathway has only been partially investigated (25). Reduced mammary tumorigenesis associated with decreased epithelial cell proliferation has been shown in TNF KO mice carrying the HER2/neu oncogene on a mixed FVBxC57BL/ 6 background (25).…”

“…Expression of TNF and its receptors has been shown in benign and malignant human breast tissues (24), but its role in mammary carcinogenesis and its involvement in the intrinsic inflammatory pathway has only been partially investigated (25). Reduced mammary tumorigenesis associated with decreased epithelial cell proliferation has been shown in TNF KO mice carrying the HER2/neu oncogene on a mixed FVBxC57BL/ 6 background (25). We also used the HER2/neu (p185) oncogene under the control of the mouse mammary tumor virus promoter to induce autochthonous mammary carcinomas from a different strain (26) and with the different aim of dissecting the actual role of leukocyte-produced TNF in mammary carcinogenesis.…”

Stromal Adipocyte Enhancer-binding Protein (AEBP1) Promotes Mammary Epithelial Cell Hyperplasia via Proinflammatory and Hedgehog Signaling

“…TNF␣ is integral in the initiation and progression of mammary tumors (33). Because AEBP1 enhances NF-B activity in mammary gland, we anticipated that increased TNF␣ levels in the mammary gland of AEBP1 TG mice mediate mammary hyperplasia and tumorigenesis.…”