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A circRNA-mRNA pairing mechanism regulates tumor growth and endocrine therapy resistance in ER-positive breast cancer

ABSTRACT: The molecular mechanisms underlying estrogen receptor (ER)-positive breast carcinogenesis and drug resistance remain incompletely understood. Elevated expression of CCND1 is linked to enhanced invasiveness, poorer prognosis, and resistance to drug therapies in ER-positive breast cancer. In this study, we report that a highly expressed circular RNA (circRNA) derived from FOXK2, called circFOXK2, stabilizes CCND1 mRNA, thereby promoting cell cycle progression, cell growth, and endocrine therapy resistance in ER-positive breast cancer cells. Mechanistically, circFOXK2 binds directly to CCND1 mRNA via RNA-RNA pairing, recruiting the RNA-binding protein ELAVL1/HuR to stabilize CCND1 mRNA, thereby increasing CCND1 protein levels. Elevated CCND1 activates the CCND1-CDK4/6-p-RB-E2F signaling axis, driving the transcription of downstream E2F target genes and promoting the G1/S transition during cell cycle progression. Consequently, anti-sense oligonucleotide (ASO)-targeting circFOXK2 (ASO-circFOXK2) suppresses the growth of ER-positive breast cancer cells both in vitro and in vivo. Combination treatment with ASO-circFOXK2 and Tamoxifen shows synergistic effects. Moreover, ASO-circFOXK2 restores Tamoxifen sensitivity in Tamoxifen-resistant ER-positive breast cancer cells both in vitro and in vivo. The clinical relevance is underscored by the high expression of circFOXK2, which is positively correlated with that CCND1 expression in ER-positive breast cancer cell lines and clinical tumor tissues. Overall, our findings reveal the critical role of circFOXK2 in stabilizing the mRNA of the oncogene CCND1 and promoting cell cycle progression, identifying circFOXK2 as a potential therapeutic target for treating ER-positive breast cancer in clinical settings.

ORGANISM(S): Homo sapiens

PROVIDER: GSE284608 | GEO | 2024/12/25

REPOSITORIES: GEO

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Project description:Hormones and growth factors accelerate cell proliferation of breast cancer cells, and these molecules are well investigated targets for drug development and application. The mechanisms of cell proliferation of breast cancers lacking estrogen receptor (ER) and HER2 have not been fully understood. The purpose of the present study is to find genes that are differentially expressed in breast cancers and that might significantly contribute to cell proliferation in these cancers. Forty tumor samples, consisting of ten each of immunohistochemically ER(+)/HER2(-), ER(+)/HER2(+), ER(-)/HER2(+), and ER(-)/HER2(-) cancer were analyzed using oligonucleotide microarrays. Both genes and tumor samples were subjected to hierarchical clustering. ER(+)/HER2(-) breast cancers and ER(-)/HER2(-) cancers tended to form a tumor cluster, but HER2 positive breast cancers were split into different tumor clusters. Significant differential expression between IHC-ER(-)/HER2(-) and other tumors was defined as having an expression level at least 2-fold higher or 2-fold lower, and analyzed by multi-step two-way ANOVA. Genes overexpressed differently in IHC-ER(-)/HER2(-) breast cancers compared to other all three types were 8 genes (FABP7, GABRP, GAL, CXCL13, CDC42EP4, C2F, FOXM1, CSDA), and underexpressed genes were nine including ITGB5, KIAA0310, MAGED2, PRSS11, SORL1, TGFB3, KRT18, CPE, BCAS1. No gene was directly related to cell proliferation such as cyclins, cyclin-dependent kinase, p53, p16, and the pRb and p21 families. We had a particular focus on a transcriptional factor E2F-5 from a list of genes overexpressed in ER negative breast cancers compared to ER positive breast cancers, and further examined. Gene amplification of E2F-5 was detected in 5/57 (8.8%) in breast cancers by FISH. No point mutation was found at the binding domain with DNA or dimerization partner of E2F-5. Immunohistochemically E2F-5 positive cancers were more frequent in ER(-)/HER2(-) cancer (14/27, 51.9%) than in other types of cancer (5/30, 16.7%) (p=0.05). E2F-5 positive cancers had higher Ki-67 labeling index (59.5%) than E2F-5 negative cancers (36.3%). E2F-5 positive cancers showed higher histological grade including metaplastic carcinoma, and worse clinical outcome with shorter disease free survival in node negative patients. In conclusion, we demonstrated that there is a population of breast cancer with overexpression of a cell cycle related transcriptional factor E2F-5. E2F-5 positive breast cancers were frequent in ER(-)/HER2(-) group with high Ki-67 labeling index, high histological grade and worse clinical outcome. Keywords: immunohistochemical phenotype

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A circRNA-mRNA pairing mechanism regulates tumor growth and endocrine therapy resistance in ER-positive breast cancer

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