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

Oncogene. 2020 Jan;39(1):64-78. doi: 10.1038/s41388-019-0959-3. Epub 2019 Aug 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / radiotherapy
  • Brain Neoplasms / secondary
  • Breast Neoplasms / genetics*
  • 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 / pathology*
  • Neoplastic Stem Cells / radiation effects
  • Octamer Transcription Factor-3 / genetics
  • Receptor, ErbB-2 / genetics
  • SOXB1 Transcription Factors / genetics
  • Transcription Factors / genetics*
  • Tumor Microenvironment / genetics
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein GLI1 / metabolism*

Substances

  • GLI1 protein, human
  • Hyaluronan Receptors
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Transcription Factors
  • Zinc Finger Protein GLI1
  • ERBB2 protein, human
  • Receptor, ErbB-2