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We performed ChIP-seq for TLE3 in MDA-MB-453 cells with and without FOXA1 transient silencing (siFOXA1 vs siNS) to determine the requirement of FOXA1 for TLE3 binding.

ABSTRACT: The identification of mechanisms controlling breast tumor progression from less aggressive to highly metastatic disease should provide novel therapeutic targets for patients. Here we report the transcriptional corepressor, TLE3, as a critical regulator of cellular plasticity in breast cancer. TLE3 facilitates repression of genes associated with the highly aggressive basal-like breast cancer (BLBC) subtype within luminal cells. Additionally, maintenance of the luminal lineage is dependent on appropriate localization of TLE3 to its transcriptional targets which is mediated through interaction with FOXA1. Furthermore, the ability of TLE3 to repress BLBC transcription results in reduced metastatic capacity and aggressive cellular behaviors. Together our findings establish TLE3 as a critical transcriptional mediator of breast cancer aggressiveness, with TLE3 sustaining the more differentiated and less metastatic nature of luminal tumors through suppression of gene expression programs associated with BLBC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205862 | GEO | 2023/02/07

REPOSITORIES: GEO

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TLE3 drives luminal identity of breast cancer through transcriptional repression of FOXA1-target genes

Project description:The identification of mechanisms controlling breast tumor progression from less aggressive to highly metastatic disease should provide novel therapeutic targets for patients. Here we report the transcriptional corepressor, TLE3, as a critical regulator of cellular plasticity in breast cancer. TLE3 facilitates repression of genes associated with the highly aggressive basal-like breast cancer (BLBC) subtype within luminal cells. Additionally, maintenance of the luminal lineage is dependent on appropriate localization of TLE3 to its transcriptional targets which is mediated through interaction with FOXA1. Furthermore, the ability of TLE3 to repress BLBC transcription results in reduced metastatic capacity and aggressive cellular behaviors. Together our findings establish TLE3 as a critical transcriptional mediator of breast cancer aggressiveness, with TLE3 sustaining the more differentiated and less metastatic nature of luminal tumors through suppression of gene expression programs associated with BLBC.

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Project description:Lineage plasticity plays an important role in the development of basal-like breast cancer (BLBC), an aggressive cancer subtype. Although studies suggest BLBC is likely to originate from luminal progenitor cells, it acquires substantial basal cell features and contains a heterogenous collection of cells exhibiting basal, luminal and bipotent phenotypes. Why luminal progenitors are prone to BLBC transformation and what drives luminal-to-basal/bipotent reprogramming remains unclear. Here we show that the transcription factor SOX9 acts as a determinant for ER– luminal stem/progenitor cells (LSPCs). SOX9 controls LSPC activity in part by activating both canonical and non-canonical NF-B signaling. Inactivation of p53 and Rb in a BLBC mouse tumor model leads to upregulation of SOX9, which drives luminal-to-bipotent reprogramming in vivo. SOX9 deletion inhibits the progression of benign, neoplastic lesions to invasive carcinoma. Furthermore, SOX9 is overexpressed and correlated with shorter relapse-free survival in human BLBC. These data show that ER– LSPC determinant SOX9 acts as a lineage-specific driver for BLBC transformation.

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Project description:Lineage plasticity plays an important role in the development of basal-like breast cancer (BLBC), an aggressive cancer subtype. Although studies suggest BLBC is likely to originate from luminal progenitor cells, it acquires substantial basal cell features and contains a heterogenous collection of cells exhibiting basal, luminal and bipotent phenotypes. Why luminal progenitors are prone to BLBC transformation and what drives luminal-to-basal/bipotent reprogramming remains unclear. Here we show that the transcription factor SOX9 acts as a determinant for ER– luminal stem/progenitor cells (LSPCs). SOX9 controls LSPC activity in part by activating both canonical and non-canonical NF-KB signaling. Inactivation of p53 and Rb in a BLBC mouse tumor model leads to upregulation of SOX9, which drives luminal-to-bipotent reprogramming in vivo. SOX9 deletion inhibits the progression of benign, neoplastic lesions to invasive carcinoma. Furthermore, SOX9 is overexpressed and correlated with shorter relapse-free survival in human BLBC. These data show that ER– LSPC determinant SOX9 acts as a lineage-specific driver for BLBC transformation.

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