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2.
Cancers (Basel) ; 14(17)2022 Aug 31.
Article in English | MEDLINE | ID: mdl-36077791

ABSTRACT

The goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. To identify compounds that selectively kill tGLI1-expressing breast cancer, we screened 1527 compounds using two sets of isogenic breast cancer and brain-tropic breast cancer cell lines engineered to stably express the control, GLI1, or tGLI1 vector, and identified the FDA-approved antifungal ketoconazole (KCZ) to selectively target tGLI1-positive breast cancer cells and breast cancer stem cells, but not tGLI1-negative breast cancer and normal cells. KCZ's effects are dependent on tGLI1. Two experimental mouse metastasis studies have demonstrated that systemic KCZ administration prevented the preferential brain metastasis of tGLI1-positive breast cancer and suppressed the progression of established tGLI1-positive BCBM without liver toxicities. We further developed six KCZ derivatives, two of which (KCZ-5 and KCZ-7) retained tGLI1-selectivity in vitro. KCZ-7 exhibited higher blood-brain barrier penetration than KCZ/KCZ-5 and more effectively reduced the BCBM frequency. In contrast, itraconazole, another FDA-approved antifungal, failed to suppress BCBM. The mechanistic studies suggest that KCZ and KCZ-7 inhibit tGLI1's ability to bind to DNA, activate its target stemness genes Nanog and OCT4, and promote tumor proliferation and angiogenesis. Our study establishes the rationale for using KCZ and KCZ-7 for treating and preventing BCBM and identifies their mechanism of action.

4.
Aging (Albany NY) ; 13(3): 3290-3312, 2021 02 06.
Article in English | MEDLINE | ID: mdl-33550279

ABSTRACT

Oncogene-induced senescence (OIS) is characterized by increased expression of the cell cycle inhibitor p16, leading to a hallmark cell cycle arrest. Suppression of p16 in this context drives proliferation, senescence bypass, and contributes to tumorigenesis. OIS cells are also characterized by the expression and secretion of a widely variable group of factors collectively termed the senescence-associated secretory phenotype (SASP). The SASP can be both beneficial and detrimental and affects the microenvironment in a highly context-dependent manner. The relationship between p16 suppression and the SASP remains unclear. Here, we show that knockdown of p16 decreases expression of the SASP factors and pro-inflammatory cytokines IL6 and CXCL8 in multiple models, including OIS and DNA damage-induced senescence. Notably, this is uncoupled from the senescence-associated cell cycle arrest. Moreover, low p16 expression in both cancer cell lines and patient samples correspond to decreased SASP gene expression, suggesting this is a universal effect of loss of p16 expression. Together, our data suggest that p16 regulates SASP gene expression, which has implications for understanding how p16 modulates both the senescent and tumor microenvironment.


Subject(s)
Cellular Senescence/genetics , Cyclin-Dependent Kinase Inhibitor p16 , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Gene Knockdown Techniques , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , Lamin Type B/metabolism
5.
Oncogene ; 39(42): 6589-6605, 2020 10.
Article in English | MEDLINE | ID: mdl-32929154

ABSTRACT

Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are particularly aggressive and associated with unfavorable prognosis. TNBC lacks effective treatments. HER2-positive tumors have treatment options but often acquire resistance to HER2-targeted therapy after initial response. To address these challenges, we determined whether novel combinations of JAK2-STAT3 and SMO-GLI1/tGLI1 inhibitors synergistically target TNBC and HER2 breast cancer since these two pathways are concurrently activated in both tumor types and enriched in metastatic tumors. Herein, we show that novel combinations of JAK2 inhibitors (ruxolitinib and pacritinib) with SMO inhibitors (vismodegib and sonidegib) synergistically inhibited in vitro growth of TNBC and HER2-positive trastuzumab-resistant BT474-TtzmR cells. Synergy was also observed against breast cancer stem cells. To determine if the combination is efficacious in inhibiting metastasis, we treated mice with intracardially inoculated TNBC cells and found the combination to inhibit lung and liver metastases, and prolong host survival without toxicity. The combination inhibited orthotopic growth, VEGF-A expression, and tumor vasculature of both TNBC and HER2-positive trastuzumab-refractory breast cancer. Lung metastasis of orthotopic BT474-TtzmR xenografts was suppressed by the combination. Together, our results indicated that dual targeting of JAK2 and SMO resulted in synergistic suppression of breast cancer growth and metastasis, thereby supporting future clinical testing.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Janus Kinase 2/antagonists & inhibitors , Signal Transduction/drug effects , Smoothened Receptor/antagonists & inhibitors , Triple Negative Breast Neoplasms/drug therapy , Alternative Splicing , Anilides/pharmacology , Anilides/therapeutic use , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biphenyl Compounds/pharmacology , Biphenyl Compounds/therapeutic use , Bridged-Ring Compounds/pharmacology , Bridged-Ring Compounds/therapeutic use , Cell Line, Tumor , Drug Resistance, Neoplasm , Drug Synergism , Female , Humans , Janus Kinase 2/metabolism , Mice , Neoplasm Metastasis/drug therapy , Neoplasm Metastasis/pathology , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Nitriles , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyridines/pharmacology , Pyridines/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Receptor, ErbB-2/metabolism , STAT3 Transcription Factor/metabolism , Smoothened Receptor/metabolism , Trastuzumab/pharmacology , Trastuzumab/therapeutic use , Triple Negative Breast Neoplasms/pathology , Xenograft Model Antitumor Assays , Zinc Finger Protein GLI1/genetics , Zinc Finger Protein GLI1/metabolism
6.
Oncogene ; 39(1): 64-78, 2020 01.
Article in English | MEDLINE | ID: mdl-31462709

ABSTRACT

Mechanisms for breast cancer metastasis remain unclear. Whether truncated glioma-associated oncogene homolog 1 (TGLI1), a transcription factor known to promote angiogenesis, migration and invasion, plays any role in metastasis of any tumor type has never been investigated. In this study, results of two mouse models of breast cancer metastasis showed that ectopic expression of TGLI1, but not GLI1, promoted preferential metastasis to the brain. Conversely, selective TGLI1 knockdown using antisense oligonucleotides led to decreased breast cancer brain metastasis (BCBM) in vivo. Immunohistochemical staining showed that TGLI1, but not GLI1, was increased in lymph node metastases compared to matched primary tumors, and that TGLI1 was expressed at higher levels in BCBM specimens compared to primary tumors. TGLI1 activation is associated with a shortened time to develop BCBM and enriched in HER2-enriched and triple-negative breast cancers. Radioresistant BCBM cell lines and specimens expressed higher levels of TGLI1, but not GLI1, than radiosensitive counterparts. Since cancer stem cells (CSCs) are radioresistant and metastasis-initiating cells, we examined TGLI1 for its involvement in breast CSCs and found TGLI1 to transcriptionally activate stemness genes CD44, Nanog, Sox2, and OCT4 leading to CSC renewal, and TGLI1 outcompetes with GLI1 for binding to target promoters. We next examined whether astrocyte-priming underlies TGLI1-mediated brain tropism and found that TGLI1-positive CSCs strongly activated and interacted with astrocytes in vitro and in vivo. These findings demonstrate, for the first time, that TGLI1 mediates breast cancer metastasis to the brain, in part, through promoting metastasis-initiating CSCs and activating astrocytes in BCBM microenvironment.


Subject(s)
Brain Neoplasms/genetics , Breast Neoplasms/genetics , Neoplastic Stem Cells/pathology , Transcription Factors/genetics , Zinc Finger Protein GLI1/metabolism , Animals , Astrocytes/metabolism , Astrocytes/pathology , Brain Neoplasms/pathology , Brain Neoplasms/radiotherapy , Brain Neoplasms/secondary , Breast Neoplasms/pathology , Breast Neoplasms/radiotherapy , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic/genetics , Heterografts , Humans , Hyaluronan Receptors/genetics , Lymphatic Metastasis , Mice , Nanog Homeobox Protein/genetics , Neoplastic Stem Cells/radiation effects , Octamer Transcription Factor-3/genetics , Receptor, ErbB-2/genetics , SOXB1 Transcription Factors/genetics , Tumor Microenvironment/genetics , Zinc Finger Protein GLI1/genetics
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