Abstract
The genetically heterogeneous triple-negative breast cancer (TNBC) continues to be an intractable disease, due to lack of effective targeted therapies. Gene amplification is a major event in tumorigenesis. Genes with amplification-dependent expression are being explored as therapeutic targets for cancer treatment. In this study, we have applied Analytical Multi-scale Identification of Recurring Events analysis and transcript quantification in the TNBC genome across 222 TNBC tumors and identified 138 candidate genes with positive correlation in copy number gain (CNG) and gene expression. siRNA-based loss-of-function screen of the candidate genes has validated EGFR, MYC, ASAP1, IRF2BP2, and CCT5 genes as drivers promoting proliferation in different TNBC cells. MYC, ASAP1, IRF2BP2, and CCT5 display frequent CNG and concurrent expression over 2173 breast cancer tumors (cBioPortal dataset). More frequently are MYC and ASAP1 amplified in TNBC tumors (>30%, n = 320). In particular, high expression of ASAP1, the ADP-ribosylation factor GTPase-activating protein, is significantly related to poor metastatic relapse-free survival of TNBC patients (n = 257, bc-GenExMiner). Furthermore, we have revealed that silencing of ASAP1 modulates numerous cytokine and apoptosis signaling components, such as IL1B, TRAF1, AIFM2, and MAP3K11 that are clinically relevant to survival outcomes of TNBC patients. ASAP1 has been reported to promote invasion and metastasis in various cancer cells. Our findings that ASAP1 is an amplification-dependent TNBC driver gene promoting TNBC cell proliferation, functioning upstream apoptosis components, and correlating to clinical outcomes of TNBC patients, support ASAP1 as a potential actionable target for TNBC treatment.
Highlights
Triple-negative breast cancer (TNBC) represents a proliferative and aggressive subtype of breast cancer
Based on gene expression signatures, TNBC has been further classified into more than six molecular subtypes [29], Yet, no effective molecular targeted therapies are currently available in the clinic for this type of BC
TNBC demonstrates substantial genetic alterations [30], only two genes, TP53 and PIK3CA, have been found with mutation frequency in ~10% of TNBC patient tumors [6], indicating other driver mutations involved in TNBC progression
Summary
Triple-negative breast cancer (TNBC) represents a proliferative and aggressive subtype of breast cancer. Changes in gene copy number result in Integrative analysis of genomic amplification-dependent expression and loss-of-function screen. Copy number gains (CNGs), increasing from the two DNA copies present in normal diploid genome, sometimes to several hundred copies (known as amplification), are observed to frequently occur on cancer driver genes [8, 9]. Oncogenic driver genes with increase in DNA copy number and expression have been identified and explored as potential drug targets for targeted therapies in cancer [10]. We applied the Analytical Multi-scale Identification of Recurring Events (ADMIRE) algorithm to identify candidate driver genes that are frequently amplified by recurrent CNGs, in correlation with their RNA expression levels, in 222 triple-negative tumors from TCGA (n = 118) [15] and Metabric (n = 104) [2] datasets. Our work discovered ASAP1 as an amplification-dependent gene driving TNBC proliferation, survival and progression, supporting the potentiality of ASAP1 as a therapeutic target for the treatment of TNBC
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