CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer

Abstract

Currently, breast cancer (BRCA) has become the most common cancer in the world, whose pathological mechanism is complex. Among its subtypes, triple-negative breast cancer (TNBC) has the worst prognosis. With the increasing number of diagnosed TNBC patients, the urgent need of novel biomarkers is also rising. Cyclin-dependent kinase inhibitor 2A (CDKN2A) has recently emerged as a key regulator associated with ferroptosis and cuproptosis (FAC) and has exhibited a significant effect on BRCA, but its detailed mechanism remains elusive. Herein, we conducted the first converge comprehensive landscape analysis of FAC-related gene CDKN2A in BRCA and disclosed its prognostic value in BRCA. Then, an unsupervised cluster analysis based on CDKN2A-correlated genes unveiled three subtypes, namely cold-immune subtype, IFN-γ activated subtype and FTL-dominant subtype. Subsequent analyses depicting hallmarks of tumor microenvironment (TME) among three subtypes suggested strong association between TNBC and CDKN2A. Given the fact that the most clinically heterogeneous TNBC always displayed the most severe outcomes and lacked relevant drug targets, we further explored the potential of immunotherapy for TNBC by interfering CDKN2A and constructed the CDKN2A-derived prognostic model for TNBC patients by Lasso-Cox. The 21-gene–based prognostic model showed high accuracy and was verified in external independent validation cohort. Moreover, we proposed three drugs for TNBC patients based on our model via targeting epidermal growth factor receptor. In summary, our study indicated the potential of CDKN2A as a pioneering prognostic predictor for TNBC and provided a rationale of immunotherapy for TNBC, and offered fresh perspectives and orientations for cancer treatment via inducing ferroptosis and cuproptosis to develop novel anti-cancer treatment strategies.

DNA methylation age in paired tumor and adjacent normal breast tissue in Chinese women with breast cancer

“…For example, although transient cell senescence, which is indicative of functional p53 signaling in response to many forms of DNA damage, is recognized as a tumor suppressor mechanism, persistent senescence accompanied by p53 inactivation would promote a senescence-associated secretory phenotype (SASP), which stimulates the secretion of numerous proinflammatory cytokines and growth factors that may modulate the epigenome and disrupt normal tissue structure and function [ 20 ]. In our study, we indeed observed a significantly higher expression of CDKN2A , a cell senescence marker, in basal-like tumors as compared to tumors of other subtypes, a finding that we replicated in TCGA breast (Additional file 3 : Figure S3) and was reported by Cheng et al using TCGA data [ 21 ]. In addition, oncogene-induced senescent cells could also re-enter the cell cycle and present with a much higher tumor initiation potential (enhanced cancer-cell stemness), resulting in a highly aggressive tumor phenotype [ 22 ], such as basal-like tumors.…”

Cuproptosis: mechanisms and links with cancers

“…In the past, studies have focused on the tumor suppressor gene role of CDKN2A, and mutations of which led to loss of growth control in breast cancer(BRCA) [ 112 ], HNSC [ 113 ] and ovarian cancer cells [ 114 ], but its role in cuproptosis remains to be further investigated. CDKN2A was suggested to be highly expressed in BRCA and LUAD, and in addition, high CDKN2A expression was thought to correlate with immune cell infiltration levels [ 116 , 117 ].…”

Prognostic Significance of Cuproptosis-Related Gene Signatures in Breast Cancer Based on Transcriptomic Data Analysis

“…To be specific, excessive deposition of intracellular copper can induce fatty acylated dihydrofatamide s-Acetyltransferase (DLAT) aggregates and affects the TCA cycle, resulting in proteotoxic stress and, consequently, cell death [ 13 ]. Moreover, since other studies have suggested the close relationship between cuproptosis and breast cancer [ 25 ], we speculate that the induction of cuproptosis in breast carcinomas may become a new avenue for treating breast cancer.…”