Abstract
Background
Breast cancer is one of the most common malignant tumors in women. Cell division cycle associated 5 (CDCA5), a master regulator of sister chromatid cohesion, was reported to be upregulated in several types of cancer. Here, the function and regulation mechanism of CDCA5 in breast cancer were explored.
Methods
CDCA5 expression was identified through immunohistochemistry staining in breast cancer specimens. The correlation between CDCA5 expression with clinicopathological features and prognosis of breast cancer patients was analyzed using a tissue microarray. CDCA5 function in breast cancer was explored in CDCA5-overexpressed/knockdown cells and mice models. Co-IP, ChIP and dual-luciferase reporter assay assays were performed to clarify underlying molecular mechanisms.
Results
We found that CDCA5 was expressed at a higher level in breast cancer tissues and cell lines, and overexpression of CDCA5 was significantly associated with poor prognosis of patients with breast cancer. Moreover, CDCA5 knockdown significantly suppressed the proliferation and migration, while promoted apoptosis in vitro. Mechanistically, we revealed that CDCA5 played an important role in promoting the binding of E2F transcription factor 1 (E2F1) to the forkhead box M1 (FOXM1) promoter. Furthermore, the data of in vitro and in vivo revealed that depletion of FOXM1 alleviated the effect of CDCA5 overexpression on breast cancer. Additionally, we revealed that the Wnt/β-catenin signaling pathway was required for CDCA5 induced progression of breast cancer.
Conclusions
We suggested that CDCA5 promoted progression of breast cancer via CDCA5/FOXM1/Wnt axis, CDCA5 might serve as a novel therapeutic target for breast cancer treatment.
Background
Breast cancer is one of the most common malignant tumors in women [1]. The incidence of breast cancer accounts for more than 11.6% of female tumors, which is second only to uterine cancer in women [2]. Surgery, radiotherapy and chemotherapy are still the main therapy methods for breast cancer, while they are only suitable for patients in early stage, and have the limitations of easy recurrence and large side effects [3, 4]. Recently, results of phase III clinical trials have shown that immune checkpoint inhibitors, such as atezolizumab and pembrolizumab, are well-tolerated in combination with chemotherapy, benefit for progression-free survival of patients with triple-negative breast cancer (TNBC) [5, 6]. These findings suggest that immunotherapy emerges as a viable treatment strategy for breast cancer. However, immune checkpoint inhibitors alone exhibit modest clinical activity in advanced breast cancer, thus develo** more active combinatorial modalities and more effective biomarkers are needed to increase survival rate of patients with breast cancer [7]. Therefore, there is a critical need to uncover novel and effective therapeutic targets to improve survival rate of breast cancer patients.
Cell division cycle associated 5 (CDCA5), also termed as sororin, is a master regulator of sister chromatid cohesion and separation [8]. CDCA5 plays pivotal role in stabilizing cohesion of chromatids during S and G2/M cell cycle phases, as well as maintaining and repairing stability of DNA strands during G2 phases [9,10,11]. In recent years, CDCA5 was reported to function as a tumor promoter in various tumors, including bladder cancer, hepatocellular carcinoma [12, 13], gastric cancer [14, 15] and esophageal squamous cell carcinoma [16], as well as the breast cancer [35]. However, traditional therapy regimens of surgery, radiotherapy and chemotherapy for breast cancer have limited effects on patients with advanced breast cancer [36, 37]. It is reported that the combination therapy, such as combination of immune checkpoint inhibitors and targeted agents showed great therapeutic effect that can effectively prolong the survival of breast cancer patients [38, 39]. However, most of the existing targeted agents for breast cancer have the limitations of high recurrence rates [38]. Therefore, we here aimed to unveil the pathogenesis of breast cancer and searched for a novel therapeutic target to improve patient outcomes.
CDCA5 was initially identified as a substrate of the anaphase-promoting complex, playing an essential role in regulating the cell cycle [10]. Additionally, CDCA5 has been implicated in several tumor progressions, including bladder cancer, hepatocellular carcinoma, gastric cancer and esophageal squamous cell carcinoma [12,13,14,15,16]. Importantly, CDCA5 expression was also found to be upregulated in patients with breast cancer and the breast cancer cell lines. In an agreement, we confirmed that CDCA5 was significantly overexpressed in human breast cancer tissues and cell lines as compared with corresponding controls. Moreover, recent studies suggested that overexpression of CDCA5 was an indicator of poor prognosis of patients with hepatocellular carcinoma [20, 40] and breast cancer [21]. Consistently, we revealed that upregulation of CDCA5 was associated with tumor size and tumor metastasis in breast cancer patients, as well as the poor survival. These findings indicated the possibility of CDCA5 as a promising target for breast cancer therapy.
On the other hand, it was demonstrated that CDCA5 knockdown could dramatically inhibit cell proliferation, migration and in vivo tumorigenesis in breast cancer [17, 18]. Additionally, CDCA5 was also involved in cell cycle control in breast cancer [21]. Similarly, our results indicated that CDCA5 knockdown significantly decreased cell viability, colony formation, cell migration and promoted cell apoptosis in breast cancer. CDCA5 overexpression led to an increase of S-phase cells proportion. Therefore, we showed that CDCA5 acted as a tumor promoter in breast cancer progression. However, the underlying mechanism by which how CDCA5 facilitates breast cancer remains unclear.
To further uncover the mechanism of CDCA5 contributing to breast cancer progression, the RNA-Seq analysis was performed using CDCA5-depleted and CDCA5-control cell specimens. The data suggested that FOXM1 was one of co-expressed with CDCA5 and was apparently downregulated at both mRNA and protein levels upon CDCA5 knockdown. Moreover, FOXM1 was identified as a potential downstream target of CDCA5 by analysis of IPA interaction network. Forkhead box M1 (FOXM1) is a member of the Forkhead box (Fox) protein family characterized by a master regulator of cell survival, self-renewal, and tumorigenesis in various cancer cells [41]. FOXM1 is well known to be a transcription factor that upregulated in a plethora of tumors and targeting FOXM1 is considered as a promising therapeutic strategy for human solid cancers [42]. In breast cancer, FOXM1 has been observed at elevated levels and is known to promote breast cancer cell stemness and migration in a YAP1-dependent manner [43]. Moreover, increased expression of FOXM1 has been associated with a poor prognosis for patients with breast cancer [44, 45], aligning with our results of bioinformatics. The transcription of FOXM1 was regulated by several transcription factors, such as cAMP responsive element-binding protein (CREB), signal transducer and activator of transcription 3 (STAT3), CCCTC-binding factor (CTCF), as well as E2F can interact directly with binding sites of FOXM1 to upregulate FOXM1 expression [46,47,48,49]. By STRING database, we found the potential protein interactions between CDCA5 and E2F1, and which was validated by further Co-IP experiments in MDA-MB-231 cells. In addition, we found that the E2F1 was recruited to the FOXM1 promoter region, indicating that CDCA5 was capable to affect FOXM1 expression via binding to E2F1, thereby promoting in the progression of breast cancer. It is worth noting that Chen et al. found that E2F1 can also induce the expression of CDCA5 [13]. Combined with our research results, CDCA5 may upregulate FOXM1 transcription by interacting with E2F1. Therefore, we also speculate that the interaction between CDCA5, E2F1, and FOXM1 may form a regulatory feedback loop. High expression of CDCA5 promotes FOXM1 expression through E2F1, and high expression of FOXM1 further induces upregulation of CDCA5 expression. This regulatory model warrants further investigation and validation.
Additionally, FOXM1 was reported to activate Wnt/β-catenin signaling pathway in breast cancer, thus promoted proliferation, invasion and epithelial-mesenchymal transition of breast cancer cells [33]. However, whether Wnt/β-catenin signaling was required for CDCA5 mediated breast cancer progression was still unclear. Herein, we found that the protein expression of Wnt3a, β-catenin and the targeted protein c-Myc was decreased along with CDCA5 depletion, and which was enhanced by C59, an inhibitor of Wnt/β-catenin signaling. Moreover, the inhibition of cell viability or promotion of apoptosis induced by CDCA5 knockdown was more obvious in the presence of C59. Therefore, we showed that Wnt/β-catenin signaling may serve as the possible downstream of FOXM1 in breast cancer progression.
In summary, we identified that CDCA5 was significantly upregulated in breast cancer and it predicted poor survival of breast cancer patients. Especially, CDCA5 promoted proliferation, migration and inhibited apoptosis of breast cancer cells, which was alleviated by silencing FOXM1. The promoting role of CDCA5 was achieved by E2F1 transcriptional regulation of FOXM1 and activation of Wnt/β-catenin signaling (Fig. 6F). Therefore, we suggested that CDCA5 promoted progression of breast cancer via CDCA5/FOXM1/Wnt axis for the first time, CDCA5 may serve as a novel therapeutic target for breast cancer treatment. However, the role of CDCA5 was not investigated in the context of interactions with immune cells. This limitation underscores the necessity for future studies to explore the role of CDCA5 independent of immune cell involvement.
Data availability
All data generated or analysed during this study are included in this published article and these data are available from corresponding author on reasonable request.
Abbreviations
- CDCA5:
-
Cell division cycle associated 5
- E2F1:
-
E2F transcription factor 1
- FOXM1:
-
Forkhead box M1
- TNBC:
-
Triple-negative breast cancer
- TCGA:
-
The Cancer Genome Atlas
- IHC:
-
Immunohistochemical
- DAB:
-
Diaminobenzene
- ATCC:
-
American Type Culture Collection
- FBS:
-
Fetal bovine serum
- qPCR:
-
Real-time quantitative PCR
- cDNA:
-
Complementary DNA
- SDS-PAGE:
-
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
- PVDF:
-
Polyvinylidene difluoride
- HRP:
-
Horseradish peroxidase
- IPA:
-
Ingenuity Pathway Analysis
- Co-IP:
-
Co-immunoprecipitation
- SD:
-
Standard deviations
- OS:
-
Overall survival
- Fox:
-
Forkhead box
- CREB:
-
Element-binding protein
- STAT3:
-
Signal transducer and activator of transcription 3
- CTCF:
-
CCCTC-binding factor
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Acknowledgements
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Funding
This work was supported by the Wu Jie** Medical Foundation.
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Contributions
Na Shen and **angwang Zhao designed this project. Yiquan **ong, Lan Shi and Wen Yang conducted experiments, Huiqiong Zhang and Lei Li completed the data analysis. The raw data were saw and verified by Yiquan **ong and Huiqiong Zhang. Yiquan **ong wrote the manuscript which was checked by Na Shen. All authors have confirmed the submission of this manuscript.
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The present human and animal studies were all approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology and patients’ informed consent for this research was also obtained.
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Conflicts of interest
Na Shen and **angwang Zhao are co-correspondence authors for this study. The authors declare no conflicts of interest in this research.
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12967_2024_5443_MOESM1_ESM.tif
Supplementary Fig. 1. Knockdown efficacy and screening of potential downstream of CDCA5. (A) Transfection efficacy of three shCDCA5 lentivirus in MDA-MB-231 cells was determined by qPCR analysis. (B) The Hierarchical Clustering analysis of DEGs between CDCA5-depleted MDA-MB-231 cells and control cells. Red represented genes up-regulated, green represented genes downregulated. (C) The interaction network of CDCA5 and molecules in AMPK signaling, ATM signaling, Breast cancer regulation by stathmin1, Senescence pathway. (D) FOXM1 mRNA expression in breast cancer cell lines (MDA-MB-231, BT-549 and T47D) and the normal MCF-10 A cell line was detected by qPCR analysis. (E) STRING analysis revealed protein interactions between CDCA5 and its potential transcription factors, including ATM, E2F1, FLT1, FOXO3, MYC, SP1 and TP53. The colored nodes represented query proteins and first shell of interactions. Line color indicated the type of interaction evidence. Results were presented as mean ± SD. *p < 0.05, ***p < 0.001
12967_2024_5443_MOESM5_ESM.tif
Supplementary Fig. 2. Clinical information analysis of TCGA-BRCA samples. (A) CDCA5, E2F1 and FOXM1 gene expression in human BRCA tissues (n = 1095) and normal solid tissues (n = 113) from TCGA. (B) Overall survival in TCGA-BRCA patients with high and low expression level of CDCA5, E2F1 and FOXM1 genes alone or in combination
12967_2024_5443_MOESM6_ESM.tif
Supplementary Fig. 3. Clinical information analysis of TCGA-BRCA samples and correlation analysis between CDCA5, E2F1, FOXM1. (A) CDCA5, E2F1 and FOXM1 gene expression in the TCGA-BRCA tissues with different tumor stage. (B) Pearson correlation analysis between CDCA5, E2F1 and FOXM1 expression
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**ong, Y., Shi, L., Li, L. et al. CDCA5 accelerates progression of breast cancer by promoting the binding of E2F1 and FOXM1. J Transl Med 22, 639 (2024). https://doi.org/10.1186/s12967-024-05443-w
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DOI: https://doi.org/10.1186/s12967-024-05443-w