期刊
COMMUNICATIONS BIOLOGY
卷 4, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s42003-021-01929-1
关键词
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资金
- Department of Defense Breast Cancer Research Program [BC120894]
- Cancer Prevention and Research Institute of Texas [RP100348, RP150700]
- National Institute of Health [HD08188, HD07857]
- Adrienne Helis Malvin Foundation
- NIH [S10OD018033, S10OD023469]
SRC-3 is a key regulator in breast cancer tumorigenesis with its inhibitor SI-12 showing anti-proliferative activity in various cancer types. A genome-scale CRISPR-Cas9 screen was used to identify gene targets that enhance BC cell cytotoxicity in the presence of SI-12, and a parallel screen with an ER inhibitor was conducted to compare the activities of SRC-3 and ER alpha inhibition.
Steroid receptor coactivator 3 (SRC-3/NCoA3/AIB1), is a key regulator of gene transcription and it plays a central role in breast cancer (BC) tumorigenesis, making it a potential therapeutic target. Beyond its function as an important regulator of estrogen receptor transcriptional activity, SRC-3 also functions as a coactivator for a wide range of other transcription factors, suggesting SRC-3 inhibition can be beneficial in hormone-independent cancers as well. The recent discovery of a potent SRC-3 small molecule inhibitor, SI-2, enabled the further development of additional related compounds. SI-12 is an improved version of SI-2 that like SI-2 has anti-proliferative activity in various cancer types, including BC. Here, we sought to identify gene targets, that when inhibited in the presence of SI-12, would lead to enhanced BC cell cytotoxicity. We performed a genome-scale CRISPR-Cas9 screen in MCF-7 BC cells under conditions of pharmacological pressure with SI-12. A parallel screen was performed with an ER inhibitor, fulvestrant, to shed light on both common and distinct activities between SRC-3 and ER alpha inhibition. Bearing in mind the key role of SRC-3 in tumorigenesis of other types of cancer, we extended our study by validating potential hits identified from the MCF-7 screen in other cancer cell lines. Using a CRISPR-based large-scale screen, Gilad et al. identify the genes that show synthetic lethality with an SRC-3 inhibitor in breast cancer cells while contrasting this with the estrogen receptor degrader fulvestrant. This study provides insights into the development of therapeutic strategies for cancer forms that involve SRC-3.
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