Embryonic transcription factor SOX9 drives breast cancer endocrine resistance

Abstract

The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2-ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

“…We found that ADHFE1 upregulates intracellular D-2HG under hypoxic conditions, reaching a 5-to 15-fold increase over baseline in cell culture experiments, providing a potentially new mechanism of D-2HG accumulation in breast cancer. We also observed that L-2HG increased in breast epithelial cells that were cultured under hypoxia (data state that promotes metastasis-seeding abilities, Wnt signaling, and breast cancer endocrine resistance (33)(34)(35). ADHFE1 may also affect the DNA methylation state of cells, as 2HG is an inhibitor of 5-methylcytosine hydroxylases (36).…”

SOX9 Transcriptionally Regulates mTOR-Induced Proliferation of Basal Cell Carcinomas

“…SOX9 also contributes to the maintenance of stem/progenitor cells in the liver, pancreas, and hair follicles (Furuyama et al, 2011, Vidal et al, 2005). Consequently, dysregulated SOX9 expression has been linked to the initiation and growth of a wide range of tumors: it has been shown to enhance proliferation and migration of prostate cancer cells and the formation of pancreatic ductal adenocarcinomas and is also implicated in metastasis and endocrine resistance in breast cancer (Deng et al, 2015, Jeselsohn et al, 2017). In murine BCCs, SOX9 was recently shown to be required for tumor initiation in a Wnt/β-catenin-dependent manner (Larsimont et al, 2015).…”

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

“…HOTAIRM1 SOX9 is a stem cell factor involved in tamoxifen resistant BCa (Jeselsohn, et al 2017). HOTAIR and BCL2 expression were correlated in breast tumors and HOTAIR was shown to act as a ceRNA by base-pairing with miR-206, thus relieving mIR-206's repression of BCL2 expression (Ding, et al 2017).…”