Project description:This study is intended to investigate the differences in biological molecular expression upon HER2 status (HER2-positive and –negative) in AR-positive, ER-/PR-negative breast cancer. Results indicate that differentially expressed genes were involved in olfactory transduction, major histocompatibility complex, ECM-receptor interaction, focal adhesion, adherens junction, as well as protein processing in endoplasmic reticulum.
Project description:Estrogen receptor (ER) signaling–dependent cancer cell growth is one of the major features of ER-positive breast cancer (BC). Inhibition of ER function is a standard and effective treatment for ER-positive tumors; however, ~20% of patients with ER-positive BC experience early or late recurrence. In this study, we examined intertumor heterogeneity from an epigenetic perspective based on the hypothesis that the intrinsic difference in epigenetic states around ER signaling pathway underlies endocrine therapy resistance. We profiled chromatin accessibility data from 42 BC samples, including 35 ER-positive human epidermal growth factor receptor 2 (HER2)-negative and 7 triple-negative tumors, identifying a subgroup of ER-positive BCs with a distinctive chromatin accessibility pattern including reduced accessibility to ER-responsive elements (EREs). The same subgroup was also observed in The Cancer Genome Atlas BC cohort. Despite the reduced accessibility to EREs, the expression of ER and potential ER target genes were not decreased in these tumors. Our findings highlight the existence of a subset of ER-positive BCs with unchanged ER expression but reduced EREs accessibility that cannot be distinguished by conventional immunostaining for ER. Future studies should determine whether these tumors are associated with resistance to endocrine therapy.
Project description:RanBP2 type and C3HC4 type zinc finger containing protein 1 (RBCK1,) is a 58 kDa protein containing N-terminal ubiquitin like (UBL) domain, npl4 type zinc finger (NZF) domain and catalytic carbon terminal RBR domain. It is known that it has abnormal expression in tumors, making it a valuable diagnostic marker and drug target. A large number of studies have confirmed that in ER positive breast cancer, about 25%-40% of the tumor showed a visible hypoxia area. Under hypoxia, tumor cells can activate HIF1 pathway and widely activate the expression of downstream genes. Hypoxia inducible factor HIF-1 is composed of HIF-1α and HIF-1β Two subunits, The protein level of HIF-1α is precisely regulated by oxygen concentration. Here, we report RBCK1, a RING family ubiquitin ligase that regulates HIF1α, promoting ER positive breast cancer growth and inhibiting apoptosis. Deletion of RBCK1 inhibits ER positive breast cancer growth and promotes cell death. RNA sequencing analysis showed that in ER positive breast cancer, RBCK1 may be an important modifier of HIF1α signal pathway. Further experiments showed that RBCK1 and HIF1α Interacts and inhibits HIF1α polyubiquitination to inhibit HIF1α degradation in ER positive breast cancer cells. These finding reveals a novel direct HIF1α regulator and a potential therapeutic target for ER positive breast cancer.
Project description:Diagnostic samples from female breast cancer patients with ER-positive and HER2-normal tumors selected for neoadjuvant chemotehrapy.
Project description: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.
Project description:Using a siRNA screen we identified the histone demethylase enzyme KDM3A as a potential positive regulator of ER signalling in breast cancer. To interrogate the full extent of KDM3A regulation on ER signalling we assessed basal and estrogen (E2)- stimulated global gene expression changes in KDM3A-depleted MCF-7 cells by microarray analysis using the Illumina Human HT12 Version 4 BeadChip array. We identified ER regulated genes affected by KDM3A knockdown and determined that KDM3A is required for ER recruitment to estrogen response elements in the promotors of ER regulated genes. We also identified that KDM3A regulates expression of a number of genes involved in proliferation and that knockdown of KDM3A inhibits ER positive breast cancer cell growth.
