Expression of ANRIL–Polycomb Complexes–CDKN2A/B/ARF Genes in Breast Tumors: Identification of a Two-Gene (EZH2/CBX7) Signature with Independent Prognostic Value

Abstract

ANRIL, a long noncoding RNA (lncRNA), has recently been reported to have a direct role in recruiting polycomb repressive complexes PRC2 and PRC1 to regulate the expression of the p15/CDKN2B-p16/CDKN2A-p14/ARF gene cluster. Expression analysis of ANRIL, EZH2, SUZ12, EED, JARID2, CBX7, BMI1, p16, p15, and p14/ARF genes was evaluated in a large cohort of invasive breast carcinomas (IBC, n ¼ 456) by qRT-PCR and immunohistochemistry (IHC) was performed on CBX7, EZH2, p14, p15, p16, H3K27me3, and H3K27ac. We observed significant overexpression in IBCs of ANRIL (19.7%) and EZH2 (77.0%) and an underexpression of CBX7 (39.7%). Correlations were identified between these genes, their expression patterns, and several classical clinical and pathologic parameters, molecular subtypes, and patient outcomes, as well as with proliferation, epithelial-mesenchymal transition, and breast cancer stem cell markers. Multivariate analysis revealed that combined EZH2/ CBX7 status is an independent prognostic factor (P ¼ 0.001). In addition, several miRNAs negatively associated with CBX7 underexpression and EZH2 overexpression. These data demonstrate a complex pattern of interactions between lncRNA ANRIL, several miRNAs, PRC2/PRC1 subunits, and p15/CDKN2B-p16/CDKN2A-p14/ARF locus and suggest that their expression should be considered together to evaluate antitumoral drugs, in particular the BET bromodomain inhibitors.Implications: This study suggests that the global pattern of expression rather than expression of individual family members should be taken into account when defining functionality of repressive Polycomb complexes and therapeutic targeting potential.

Association of cyclin‐dependent kinase inhibitor 2A/B with increased risk of developing breast cancer

“…In another study, the P16 positive patients had a better response to chemotherapy than breast cancer patients with P16 negative. These findings support that the P16 may be used as a prognostic factor for the consequence and response to the treatment of the patients (Meseure et al, ).…”

A three-long noncoding RNA signature as a diagnostic biomarker for differentiating between triple-negative and non-triple-negative breast cancers

“…A recent study measured mRNA levels of the gene encoding ANRIL in 456 breast carcinomas tissues and found that ANRIL mRNA expression was higher in breast carcinomas tissues than in normal breast tissues, which was exclusively and weakly correlated with ER and PR status and showed a complex association with epithelial–mesenchymal transition markers. [31] We determined ANRIL expression in the plasma of patients with BC and found that its expression was surprisingly higher in patients with TNBC than in patients with NTNBC. These findings prompted us to determine the diagnostic value of ANRIL in TNBC, which has not been performed to date.…”

Biological function of long noncoding RNAsnaRin HER2-positive breast cancer cells

“…Similar in breast cancer, several lncRNAs such as ANRIL or UCA1 and snaR were revealed as upregulated and strongly associated with tumor progression or poor prognosis in previous studies. 12,13,[26][27][28] However, as breast cancer is an extremely heterogenic disease, these knockdown processes may not result as identical based on tumor subtypes or characteristics. Therefore, the study of biological functions of lncRNA should be conducted differently according to the subtype of breast cancer.…”