Discovery of a proliferation essential gene signature and actin-like 6A as potential biomarkers for predicting prognosis and neoadjuvant chemotherapy response in triple-positive breast cancer.

Abstract

Patients with triple-positive breast cancer (TPBC) have a higher risk of recurrence and lower survival rates than patients with other luminal breast cancers. However, there are few studies on the predictive biomarkers of prognosis and treatment responses in TPBC. Proliferation essential genes (PEGs) were acquired from clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) technology, and cohorts of patients with TPBC were obtained from public databases and our cohort. To develop a TPBC-PEG signature, Cox regression and least absolute shrinkage and selection operator regression analyses were applied. Functional analyses were performed with gene set enrichment analysis. The relationship between candidate genes and neoadjuvant chemotherapy (NACT) sensitivity was explored via real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) on the basis of clinical samples. Among 900 TPBC-PEGs, 437 showed significant differential expression between TPBC and normal tissues. Three prognostic PEGs (actin-like 6A [ACTL6A], chaperonin containing TCP1 subunit 2 [CCT2], and threonyl-TRNA synthetase [TARS]) were identified and used to construct the PEG signature. Patients with high PEG signature scores exhibited a worse overall survival and lower sensitivity to NACT than patients with low PEG signature scores. RT-qPCR results indicated that ACTL6A and CCT2 expression were significantly upregulated in patients who lacked sensitivity to NACT. IHC results showed that the ACTL6A protein was highly expressed in patients with NACT resistance and nonpathological complete responses. This efficient PEG signature prognostic model can predict the outcomes of TPBC. Furthermore, ACTL6A expression level was associated with the response to NACT, and could serve as an important factor in predicting prognosis and drug sensitivity of patients with TPBC.