Increased ID4 expression, accompanied by mutant p53 accumulation and loss of BRCA1/2 proteins in triple‐negative breast cancer, adversely affects survival

Abstract

There is frequent ID4 expression and concomitant loss of BRCA proteins in triple-negative breast cancer. We hypothesize that strong ID4 expression could be useful as a prognostic marker in triple-negative breast cancer, predicting early tumour recurrence.

ID4 controls luminal lineage commitment in normal mammary epithelium and inhibits BRCA1 function in basal-like breast cancer

“…BRCA1, the breast and ovarian cancer susceptibility gene, is responsible for the majority of hereditary breast cancer cases ( (Lakhani et al 2005, Turner et al 2007) and reviewed in Mavaddat et al 2010). BRCA1 and ERα mRNA expression have been shown to correlate in sporadic breast cancers (Roldán et al 2006), while ID4 is negatively correlated to both BRCA1 and ERα (Roldán et al 2006, Thike et al 2015. This phenomenon has been suggested to occur through ERα inhibition of ID4 in a luminal breast cancer cell line (Beger et al 2001).…”

“…However, the relevance is unclear, as in clinical breast cancer, ID4 expression is exclusive to ERα-negative subtypes of breast cancer (Crippa et al 2014). This evidence has led researchers to suggest that ID4 loss may be important in the development of ERα-dependent breast cancers (de Candia et al 2006), and conversely, ID4 may suppress BRCA1 and ERα in ID4-positive BLBC (Best et al 2014), resulting in poor survival outcomes (Junankar et al 2015, Thike et al 2015.…”

“…This subtype is associated with ID4 overexpression and amplification (de Candia et al 2006, Turner et al 2007. In BLBC, ID4 correlates with TP53 protein expression which associates with higher grade and risk of metastasis (Thike et al 2015). ID4 is required for the proliferation of BLBC cell lines in vitro and in vivo and marks a subset of poor prognosis BLBCs (Junankar et al 2015, Valenti et al 2015.…”

“…The majority of the literature is based on Crippa et al (2014) ID4 expression is inversely correlated with miR-342 and (Turner et al 2007, Thike et al 2015, Korlimarla et al 2016. Beger and coworkers (2001) subsequently characterised the regulators of BRCA1 gene expression and identified ID4 as an upstream regulator of the BRCA1 promoter using an inverse genomics approach in luminal breast cancer cell lines.…”

A novel role for the HLH protein Inhibitor of Differentiation 4 (ID4) in the DNA damage response in basal-like breast cancer

“…We and others have previously shown ID4 to be a master regulator of mammary stem cell self-renewal in the normal mammary gland (Junankar et al, 2015, Best et al, 2014, Dong et al, 2011), as well as important for the aetiology of BLBC. ID4 is overexpressed in a subset of BLBC patients, marking patients with poor survival outcome, and is necessary for the growth of BLBC cell lines (Beger et al, 2001, Branham et al, 2016, Crippa et al, 2014, de Candia et al, 2006, Junankar et al, 2015, Rold á n et al, 2006, Shan et al, 2003, Thike et al, 2015, Wen et al, 2012). Precisely how ID4 mediates this function in BLBC is unclear.…”