imd-0354 and Breast-Neoplasms

Development of chemoresistance in breast cancer patients greatly increases mortality. Thus, understanding mechanisms underlying breast cancer resistance to chemotherapy is of paramount importance to overcome this clinical challenge. Although activated Notch receptors have been associated with chemoresistance in cancer, the specific Notch ligands and their molecular mechanisms leading to chemoresistance in breast cancer remain elusive. Using conditional knockout and reporter mouse models, we demonstrate that tumor cells expressing the Notch ligand Dll1 is important for tumor growth and metastasis and bear similarities to tumor-initiating cancer cells (TICs) in breast cancer. RNA-seq and ATAC-seq using reporter models and patient data demonstrated that NF-κB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-κB pathway completely sensitizes Dll1

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Breast; Breast Neoplasms; Calcium-Binding Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Datasets as Topic; Disease Models, Animal; Doxorubicin; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Membrane Proteins; Mice; Mice, Knockout; Neoplastic Stem Cells; NF-kappa B p50 Subunit; Receptors, Notch; RNA-Seq; Signal Transduction

Since more than 75% of breast cancers overexpress estrogen receptors (ER), endocrine therapy targeting ER has significantly improved the survival rate. Nonetheless, breast cancer still afflicts women worldwide and the major problem behind it is resistance to endocrine therapy. We have previously shown the involvement of nuclear factor-κB (NF-κB) in neoplastic proliferation of human breast cancer cells; however, the association with the transformation of ER-positive cells remains unclear. In the current study, we focused on roles of NF-κB in the hormone dependency of breast cancers by means of ER-positive MCF-7 cells. Blocking of NF-κB signals in ER-negative cells stopped proliferation by downregulation of D-type cyclins. In contrast, the MCF-7 cells were resistant to NF-κB inhibition. Under estrogen-free conditions, the ER levels were reduced when compared with the original MCF-7 cells and the established cell subline exhibited tamoxifen resistance. Additionally, NF-κB participated in cell growth instead of the estrogen-ER axis in the subline and consequently, interfering with the NF-κB signals induced additive anticancer effects with tamoxifen. MMP-9 production responsible for cell migration, as well as the cell expansion in vivo, were suppressed by NF-κB inhibition. Therefore, we suggest that NF-κB is a master switch in both ER-positive and ER-negative breast cancers.

Topics: Animals; Antineoplastic Agents, Hormonal; Apoptosis; Benzamides; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Drug Resistance, Neoplasm; Female; Humans; Matrix Metalloproteinase 9; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Receptors, Estrogen; RNA Interference; RNA, Small Interfering; Tamoxifen; Transplantation, Heterologous

The molecular mechanisms governing acquired tumor resistance during radiotherapy remain to be elucidated. In breast cancer patients, overexpression of HER2 (human epidermal growth factor receptor 2) is correlated with aggressive tumor growth and increased recurrence. In the present study, we demonstrate that HER2 expression can be induced by radiation in breast cancer cells with a low basal level of HER2. Furthermore, HER2-postive tumors occur at a much higher frequency in recurrent invasive breast cancer (59%) compared to the primary tumors (41%). Interestingly, NF-kappaB is required for radiation-induced HER2 transactivation. HER2 was found to be co-activated with basal and radiation-induced NF-kappaB activity in radioresistant but not radiosensitive breast cancer cell lines after long-term radiation exposure, indicating that NF-kappaB-mediated HER2 overexpression is involved in radiation-induced repopulation in heterogeneous tumors. Finally, we found that inhibition of HER2 resensitizes the resistant cell lines to radiation. Since HER2 is shown to activate NF-kappaB, our data suggest a loop-like HER2-NF-kappaB-HER2 pathway in radiation-induced adaptive resistance in breast cancer cells.

Topics: Adaptation, Physiological; Animals; Benzamides; Breast Neoplasms; Cell Line, Tumor; Gamma Rays; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Humans; Mice; NF-kappa B; Phenotype; Promoter Regions, Genetic; Radiation Tolerance; Recurrence; RNA, Small Interfering; Signal Transduction; Up-Regulation

Constitutive nuclear factor-kappaB (NF-kappaB) activity plays a crucial role in the development and progression of lymphoma, leukemia, and some epithelial cancers. Given the contribution of NF-kappaB in carcinogenesis, a novel approach that interferes with its activity might have therapeutic potential against cancers that respond poorly to conventional treatments. Here, we have shown that a new IkappaB kinase beta inhibitor, IMD-0354, suppressed the growth of human breast cancer cells, MDA-MB-231, HMC1-8, and MCF-7, by arresting cell cycle and inducing apoptosis. In an electrophoretic mobility shift assay and a reporter assay, IMD-0354 abolished the NF-kappaB activity in MDA-MB-231 cells in a dose-dependent manner. In the cells incubated with IMD-0354, cell cycle arrested at the G0-G1 phase and apoptotic cells were increased. The expression of some cell cycle regulatory molecules and antiapoptotic molecules was suppressed in cells treated with IMD-0354. On the other hand, cyclin-dependent kinase suppressor p27Kip1 was up-regulated by the addition of IMD-0354. Daily administration of IMD-0354 inhibited tumor expansion in immunodeficient mice into which MDA-MB-231 cells were transplanted. These results indicate that NF-kappaB may contribute to cell proliferation through up-regulation of cell cycle progression; accordingly, inhibition of NF-kappaB activity might have a therapeutic ability in the treatment of human breast cancers.

Topics: Animals; Benzamides; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Disease Progression; Female; Humans; I-kappa B Kinase; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Protein Kinase Inhibitors; RNA, Messenger; Transforming Growth Factor beta; Xenograft Model Antitumor Assays