CITED1 as a marker of favourable outcome in anti-endocrine treated, estrogen-receptor positive, lymph-node negative breast cancer

Abstract

Objective To investigate CITED1 as a potential biomarker of anti-endocrine response and breast cancer recurrence, given its previously determined role in mediating estrogen-dependant transcription. The study is a continuation of earlier work establishing the role of CITED1 in mammary gland development. Results CITED1 mRNA is associated with estrogen-receptor positivity and selectively expressed in the GOBO dataset of cell lines and tumours representing the luminal-molecular subtype. In patients treated with tamoxifen, higher CITED1 correlated with better outcome, suggesting a role in anti-estrogen response. The effect was particularly evident in the subset of estrogen-receptor positive, lymph-node negative (ER+/LN−) patients although noticeable divergence of the groups was apparent only after five years. Tissue microarray (TMA) analysis further validated the association of CITED1 protein, by immunohistochemistry, with favourable outcome in ER+, tamoxifen-treated patients. Although we also found a favourable response to anti-endocrine treatment in a larger TCGA dataset, the tamoxifen-specific effect was not replicated. Finally, MCF7 cells overexpressing CITED1 showed selective amplification of AREG but not TGFα suggesting that maintenance of specific ERα-CITED1 mediated transcription is important for the long-term response to anti-endocrine therapy. These findings together confirm the proposed mechanism of action of CITED1 and support its potential use as a prognostic biomarker.

Roles and signaling pathways of CITED1 in tumors: overview and novel insights

“… 15 However, the latest literature confirms that MCF-7 cells overexpressing CITED1 exhibit selective amplification of AREG but not TGF-α, and the maintenance of specific ERα/CITED1-mediated transcription is a good prognostic marker in patients with anti-endocrine–treated ER+/LN- breast cancer. 28 , 30 Therefore, the role of CITED1 in regulating TGF-α transcription in MCF-7 cells remains controversial and further exploration is needed. In addition, the EGR2/CITED1 transcription factor complex can bind to the ErbB2 promoter and increase the expression of human epithelial growth factor receptor 2 (HER2).…”