TGLI1 transcription factor mediates breast cancer brain metastasis via activating metastasis-initiating cancer stem cells and astrocytes in the tumor microenvironment

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 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Hedgehog Signaling and Truncated GLI1 in Cancer

“…We have optimized conditions to reliably separate two GLI1 isoforms by SDS-PAGE and validated custom-made antibodies to specifically detect tGLI1. However, the difficulty in separating the two proteins could mean that functions previously ascribed to GLI1 are actually due to tGLI1-specific activity [25,33]. Our laboratory, and others, have shown the tGLI1 variant to be expressed in most GBM specimens and patient-derived xenografts, but undetectable in normal brain cells or tissues [24,26,27,29].…”

“…GLI1 proteins regulate the expression of the pluripotency factors Nanog, octamer binding transcription factor 4 (OCT4), SOX2, WNT-2, CD44, and Kruppel-like factor 4 (KLF4) [148,165,167,168]. Recently, we have shown the novel tGLI1 isoform to promote the glioma stem cell population via upregulation of CD44 and the breast cancer stem cell population through upregulation of CD44, Nanog, OCT4, and Sox2 (Section 6) [31,33]. These data demonstrate that amplified SHH signaling is important for the self-renewal and maintenance of CSCs.…”

HER2‐positive breast cancer brain metastasis: A new and exciting landscape

“…42 TGLI1 may also contribute to radioresistance by increasing stemness and creating a "metastasis-friendly" microenvironment through activation of astrocytes. 42 Fatty acid binding protein 7 (FABP-7) is a lipid binding protein found specifically in the brain. However, FABP-7 is also expressed in BC cells, particularly Recent progress in the field of cell-and viral-based therapeutics has also been applied to HER2+ BCBrM.…”

Low-dose Diosbulbin-B (DB) Regulates Tumor-Intrinsic PD-L1/NLRP3 Signaling Pathway to Increase Cisplatin-Sensitivity in Gastric Cancer (GC)

“…Cancer stem cells (CSCs) contributed to metastasis, recurrence and drug resistance in cancers [11][12][13][14], and previous data suggested that CSCs enrichment contributed to cisplatin-resistance in GC cells [17,18]. Therefore, elimination of CSCs will help to improve chemo-sensitivity in GC cells [19].…”

“…Cancer stem cells (CSCs) were a subgroup of cancer cells characterized by high self-renewal abilities [11,12], which sustained the heterogeneity of tumor cells and contributed to metastasis and bad prognosis in GC patients [13,14]. In addition, recent data indicated that CSCs were pivotal for sustaining cisplatinresistance in multiple cancers, such as head and neck squamous cell carcinoma (HNSCC) [15], lung cancer [16] and GC [17,18].…”