Deciphering clinical significance of BCL11A isoforms and protein expression roles in triple-negative breast cancer subtype

Abstract

Purpose: Triple negative breast cancer (TNBC) is an aggressive clinical tumor, accounting for about 25% of breast cancer (BC) related deaths. Chemotherapy is the only therapeutic option to treat TNBC, hence a detailed understanding of the biology and its categorization is required. To investigate the clinical relevance of BCL11A in TNBC subtype, we focused on gene and protein expression and its mutational status in a large cohort of this molecular subtype.

Methods: Gene expression profiling of BCL11A and its isoforms (BCL11A-XL, BCL11A-L and BCL11A-S) has been determined in Luminal A, Luminal B, HER2-enriched and TNBC subtypes. BCL11A protein expression has been analyzed by immunohistochemistry (IHC) and its mutational status by Sanger sequencing.

Results: In our study, BCL11A was significantly overexpressed in TNBC both at transcriptional and translational levels compared to other BC molecular subtypes. A total of 404 TNBCs were selected and examined showing a high prevalence of BCL11A-XL (37.3%) and BCL11A-L (31.4%) isoform expression in TNBC, associated with a 26% of BCL11A protein expression levels. BCL11A protein expression predicts scarce LIV (HR = 0.52; 95% CI, 0.29-0.92, P = 0.03) and AR downregulation (HR = 0.37; 95% CI, 0.16-0.88; P = 0.02), as well as a higher proliferative index in TNBC cells. BCL11A-L expression is associated with more aggressive TNBC histological types, such as medullary and metaplastic carcinoma.

Conclusion: Our finding showed that BCL11A protein expression acts as an unfavorable prognostic factor in TNBC patients, especially in non luminal TNBCs subgroups. These results may yield a better treatment strategy by providing a new parameter for TNBC classification.

Keywords: BCL11A expression; BCL11A isoforms; BCL11A mutations; Survival analysis; Triple negative breast cancer.

Fig. 1

Expression of BCL11A and its mRNA isoforms in molecular intrinsic subtypes of breast cancer. A Significant BCL11A expression in TNBC compared to other molecular intrinsic subtypes of breast cancer. B BCL11A mRNA expression across the molecular intrinsic subtypes of breast cancer. Mann–Whitney test was used. *p-value < 0.05; **p-value < 0.01

Fig. 2

BCL11A immunohistochemical expression in molecular intrinsic breast cancer subtypes. A Immunohistochemistry for BCL11A displaying diffuse and intense immunoreactivity in TNBC (IBC-NST, original magnification 40 ×); B Immunohistochemistry for BCL11A displaying diffuse and intense immunoreactivity in TNBC (IBC-NST, original magnification 200 ×); C Immunohistochemistry for BCL11A displaying diffuse and intense immunoreactivity in TNBC (Medullary-type carcinoma, original magnification 200 ×); D Immunohistochemistry for BCL11A displaying diffuse and intense immunoreactivity in TNBC (Metaplastic carcinoma, original magnification 40 ×); E Immunohistochemistry for BCL11A displaying diffuse and intense immunoreactivity in TNBC (adenoid cystic carcinoma, original magnification 40 ×); F Negative immunohistochemistry for BCL11A in Luminal A breast cancer (IBC-NST, original magnification 200 ×); G Negative immunohistochemistry for BCL11A in Luminal B breast cancer (IBC-NST, original magnification 200 ×); H Negative immunohistochemistry for BCL11A in HER2-enriched breast cancer (Invasive lobular carcinoma, original magnification 200 ×)

Fig. 3

Kaplan–Meier curves for overall survival according to BCL11A protein expression in all TNBC cohort