Transcriptome Analysis Identifies GATA3-AS1 as a Long Noncoding RNA Associated with Resistance to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients

Abstract

Breast cancer is one of the leading causes of mortality in women worldwide, and neoadjuvant chemotherapy has emerged as an option for the management of locally advanced breast cancer. Extensive efforts have been made to identify new molecular markers to predict the response to neoadjuvant chemotherapy. Transcripts that do not encode proteins, termed long noncoding RNAs (lncRNAs), have been shown to display abnormal expression profiles in different types of cancer, but their role as biomarkers in response to neoadjuvant chemotherapy has not been extensively studied. Herein, lncRNA expression was profiled using RNA sequencing in biopsies from patients who subsequently showed either response or no response to treatment. The GATA3-AS1 Q10 transcript was overexpressed in the nonresponder group and was the most stable feature when performing selection in multiple random forest models. GATA3-AS1 was experimentally validated by RT-qPCR Q11 in an extended group of 68 patients. Expression analysis confirmed that GATA3-AS1 is overexpressed primarily in patients who were nonresponsive to neoadjuvant chemotherapy, with a sensitivity of 92.9%, a specificity of 75.0%, and an area under the curve of approximately 0.90, as measured by receiver operating characteristic curve analysis. The statistical model was based on luminal B-like patients and adjusted by menopausal status and phenotype (odds ratio, 37.49; 95% CI, 6.74e208.42; P Z 0.001); GATA3-AS1 was established as an independent predictor of response. Thus, lncRNA GATA3-AS1 is proposed as a potential predictive biomarker of nonresponse to neoadjuvant chemotherapy. Q12

CRISPR/Cas9 screen uncovers functional translation of cryptic lncRNA-encoded open reading frames in human cancer

“…Among the identified cryptic-ORF dependencies, we validated in vitro and/or in vivo tumor-promoting functions for 2 of them that are encoded by LINC00992 and GATA3-AS1 . Interestingly, the overexpression of LINC00992 and GATA3-AS1 in tumors or cancer cell lines was previously associated with chemoresistance ( 62 , 63 ). These findings suggest that although our CRISPR screen was performed in the absence of drugs, some of the identified functional cryptic ORFs might play an important role in therapeutic resistance of ER + BC, which warrants further investigation.…”

Identification of interpretable clusters and associated signatures in breast cancer single cell data: a topic modeling approach

“…Also strongly associated with lncRNA-Topic 4 we found GATA3-AS1, a lncRNA recently proposed as predictive biomarker of nonresponsive breast cancer patients to neoadjuvant chemotherapy (29). GATA3-AS1 was described as a functional lncRNA and positive transcriptional regulator of GATA3 in TH2 lineage of lymphocytes (29).…”

“…GATA3-AS1 was described as a functional lncRNA and positive transcriptional regulator of GATA3 in TH2 lineage of lymphocytes (29).…”

Comprehensive analysis of cuproptosis-related long non-coding RNA signature and personalized therapeutic strategy of breast cancer patients

“…found that lncRNA H19 in BC could induce autophagy activation to further contribute to tamoxifen resistance ( 15 ). In the study conducted by Laura and colleagues, lncRNA GATA3-AS1 was identified as associated with resistance to neoadjuvant chemotherapy in locally advanced patients with BC ( 16 ). In addition, immunotherapy for BC has received increasing attention, such as tumor-targeting antibodies, immune checkpoint blockade, adoptive T- cell therapy, and a combination of immunotherapies and conventional chemotherapies ( 17 ).…”