Mesothelin-targeted CAR-NK Cells Derived From Induced Pluripotent Stem Cells Have a High Efficacy in Killing Triple-negative Breast Cancer Cells as Shown in Several Preclinical Models.

The emergence of immunotherapy has introduced a promising, novel approach to cancer treatment. While multiple chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable clinical efficacy against leukemia, their effect on solid tumors has been limited. One potential option for treating solid tumors is the engineering of natural killer (NK) cells with CARs. Mesothelin (MSLN), a tumor differentiation antigen, is expressed on triple-negative breast cancer (TNBC) cells, making it a potential target for CAR-NK therapy in the treatment of TNBC. We first constructed induced pluripotent stem cells with stable anti-MSLN-CAR expression and subsequently differentiated these cells into mesothelin-targeted CAR-NK (MSLN-NK) cells. We then assessed the effects of MSLN-NK cells on TNBC cells both in vitro (using the MDA-MB-231 cell line), in vivo (in a CDX mouse model), and ex vivo (using patient-specific primary cells and patient-specific organoids), in which MSLN surface expression was confirmed. Our CDX study results indicated that MSLN-NK cells effectively killed MDA-MB-231 (MD231) cells in vitro, reduced tumor growth in the CDX mouse model of TNBC, and lysed patient-specific primary cells and patient-specific organoids derived from the tumor samples of TNBC patients. Our data demonstrated that MSLN-NK cells had high efficacy on killing TNBC cells in in vitro, in vivo, and ex vivo. Therefore, MSLN-NK could be a promising treatment option for TNBC patients.

Notch3 inhibits cell proliferation and tumorigenesis and predicts better prognosis in breast cancer through transactivating PTEN.

Notch receptors (Notch1-4) play critical roles in tumorigenesis and metastasis of malignant tumors, including breast cancer. Although abnormal Notch activation is related to various tumors, the importance of single receptors and their mechanism of activation in distinct breast cancer subtypes are still unclear. Previous studies by our group demonstrated that Notch3 may inhibit the emergence and progression of breast cancer. PTEN is a potent tumor suppressor, and its loss of function is sufficient to promote the occurrence and progression of tumors. Intriguingly, numerous studies have revealed that Notch1 is involved in the regulation of PTEN through its binding to CBF-1, a Notch transcription factor, and the PTEN promoter. In this study, we found that Notch3 and PTEN levels correlated with the luminal phenotype in breast cancer cell lines. Furthermore, we demonstrated that Notch3 transactivated PTEN by binding CSL-binding elements in the PTEN promoter and, at least in part, inhibiting the PTEN downstream AKT-mTOR pathway. Notably, Notch3 knockdown downregulated PTEN and promoted cell proliferation and tumorigenesis. In contrast, overexpression of the Notch3 intracellular domain upregulated PTEN and inhibited cell proliferation and tumorigenesis in vitro and in vivo. Moreover, inhibition or overexpression of PTEN partially reversed the promotion or inhibition of cell proliferation induced by Notch3 alterations. In general, Notch3 expression positively correlated with elevated expression of PTEN, ER, lower Ki-67 index, and incidence of involved node status and predicted better recurrence-free survival in breast cancer patients. Therefore, our findings demonstrate that Notch3 inhibits breast cancer proliferation and suppresses tumorigenesis by transactivating PTEN expression.

A negative binomial regression model for risk estimation of 0-2 axillary lymph node metastases in breast cancer patients.

Extensive clinical trials indicate that patients with negative sentinel lymph node biopsy do not need axillary lymph node dissection (ALND). However, the ACOSOG Z0011 trial indicates that patients with clinically negative axillary lymph nodes (ALNs) and 1-2 positive sentinel lymph nodes having breast conserving surgery with whole breast radiotherapy do not benefit from ALND. The aim of this study is therefore to identify those patients with 0-2 positive nodes who might avoid ALND. A total of 486 patients were eligible for the study with 212 patients in the modeling group and 274 patients in the validation group, respectively. Clinical lymph node status, histologic grade, estrogen receptor status, and human epidermal growth factor receptor 2 status were found to be significantly associated with ALN metastasis. A negative binomial regression (NBR) model was developed to predict the probability of having 0-2 ALN metastases with the area under the curve of 0.881 (95% confidence interval 0.829-0.921, P < 0.001) in the modeling group and 0.758 (95% confidence interval 0.702-0.807, P < 0.001) in the validation group. Decision curve analysis demonstrated that the model was clinically useful. The NBR model demonstrated adequate discriminative ability and clinical utility for predicting 0-2 ALN metastases.

Long noncoding RNA H19 is a critical oncogenic driver and contributes to epithelial-mesenchymal transition in papillary thyroid carcinoma.

BACKGROUND: Growing evidence has indicated that the long noncoding RNA H19 (lncRNA H19), frequently deregulated in almost all tumor types tested, acted as a pivotal contributor to both cancer initiation and progression. However, the role of lncRNA H19 in human papillary thyroid carcinoma (PTC) remains controversial. The aim of the study was to investigate the expression and potential function of lncRNA H19 in human PTC. PATIENTS AND METHODS: The lncRNA H19 level was determined by quantitative real-time (RT)-PCR analyses in 58 PTC tissue samples and their paired paracancerous tissue samples. RNA interference, RT-PCR analysis, and Western blot assay were used to determine the impact of lncRNA H19 on epithelial-mesenchymal transition (EMT) markers in human PTC cells. The migratory and invasive capacities of PTC cells were determined by wound-healing and transwell migration and invasion assays. RESULTS: lncRNA H19 expression was 2.417-fold higher in PTC tissues than their paired paracancerous tissue (95% CI: 1.898-2.935, P<0.0001). Higher level of lncRNA H19 was correlated to elevated expression of Vimentin, ZEB2, Twist, and Snail2. Inhibition of lncRNA H19 resulted in upregulation of E-cadherin and downregulation of Vimentin both at mRNA and protein levels. Conversely, enforced expression of the exogenous lncRNA H19 led to E-cadherin mRNA and protein downregulation and relative upregulation of Vimentin. Moreover, wound-healing and transwell migration and invasion assays showed that lncRNA H19 could promote the migratory and invasive abilities of PTC cells. CONCLUSION: The level of lncRNA H19 was significantly higher in PTC tissues than paired paracancerous tissue or normal tissues. Overexpression of lncRNA H19 was correlated with higher tumor burden of PTC. It also contributes to EMT process, as well as promotes migration and invasion of PTC cells.

circTADA2As suppress breast cancer progression and metastasis via targeting miR-203a-3p/SOCS3 axis.

More and more evidence indicates that circular RNAs (circRNAs) have important roles in several diseases, especially in cancers. However, their involvement remains to be investigated in breast cancer. Through screening circRNA profile, we identified 235 differentially expressed circRNAs in breast cancer. Subsequently, we explored the clinical significance of two circTADA2As in a large cohort of triple-negative breast cancer (TNBC), and performed functional analysis of circTADA2A-E6 in vitro and in vivo to support clinical findings. Finally, we evaluated the effect of circTADA2A-E6 on miR-203a-3p and its target gene SOCS3. We detected two circRNAs, circTADA2A-E6 and circTADA2A-E5/E6, which were among the top five differentially expressed circRNAs in breast cancer. They were consistently and significantly decreased in a large cohort of breast cancer patients, and their downregulation was associated with poor patient survival for TNBC. Especially, circTADA2A-E6 suppressed in vitro cell proliferation, migration, invasion, and clonogenicity and possessed tumor-suppressor capability. circTADA2A-E6 preferentially acted as a miR-203a-3p sponge to restore the expression of miRNA target gene SOCS3, resulting in a less aggressive oncogenic phenotype. circTADA2As as promising prognostic biomarkers in TNBC patients, and therapeutic targeting of circTADA2As/miRNA/mRNA network may be a potential strategy for the treatment of breast cancer.

MiR-221/222 promote epithelial-mesenchymal transition by targeting Notch3 in breast cancer cell lines.

Basal-like breast cancer (BLBC) is an aggressive subtype with a strong tendency to metastasize. Due to the lack of effective chemotherapy, BLBC has a poor prognosis compared with luminal subtype breast cancer. MicroRNA-221 and -222 (miR-221/222) are overexpressed in BLBC and associate with metastasis as well as poor prognosis; however, the mechanisms by which miR-221/222 function as oncomiRs remain unknown. Here, we report that miR-221/222 expression is inversely correlated with Notch3 expression in breast cancer cell lines. Notch3 is known to be overexpressed in luminal breast cancer cells and inhibits epithelial to mesenchymal transition (EMT). We demonstrate that miR-221/222 target Notch3 by binding to its 3' untranslated region and suppressing protein translation. Ectopic expression of miR-221/222 significantly promotes EMT, whereas overexpression of Notch3 intracellular domain attenuates the oncogenic function of miR-221/222, suggesting that miR-221/222 exerts its oncogenic role by negatively regulating Notch3. Taken together, our results elucidated that miR-221/222 promote EMT via targeting Notch3 in breast cancer cell lines suggesting that miR-221/222 can serve as a potential therapeutic target in BLBC.

Prognostic values of the inhibitor of DNA­binding family members in breast cancer.

The inhibitor of DNA­binding (ID) proteins are dominant­negative modulators of transcription factors with basic helix­loop­helix (bHLH) structures, which control a variety of genes in cell cycle regulation. An increasing volume of evidence has demonstrated that the deregulated expression of IDs in several types of malignancy, including breast carcinoma, has been proven to serve crucial regulatory functions in tumorigenesis and the development of breast cancer (BC). The present study evaluated the prognostic values of the ID family members by investigating a set of publicly accessible databases, including Oncomine, bc­GenExMiner, Kaplan­Meier plotter and the Human Protein Atlas. The results demonstrated that mRNA levels of distinct IDs exhibited diverse profiles between BC and normal counterparts. The mRNA expression level of ID2 was significantly higher in breast cancer than normal tissues, while the mRNA expression levels of ID1, ID3 and ID4 were significantly lower in breast cancer tissues than in normal tissues. Furthermore, higher mRNA expression levels of ID1 and ID4 were associated with subgroups with lower pathological grades and fewer lymph node metastases. Survival analysis revealed that elevated mRNA levels of ID1 and ID4 predicted an improved survival in all patients with BC. Increased ID1 mRNA levels were associated with higher relapse­free survival rates in all patients with BC, particularly in those with ER positive and Luminal A subtype tumors. Increased ID4 mRNA expression predicted longer survival times in all patients with BC, particularly in those with hormone receptor­positive tumors or those treated with endocrine therapy. These results indicated that IDs are essential prognostic indicators in BC. Future studies on the effect of IDs on the pathogenesis and development of BC are warranted.

Notch3 inhibits epithelial-mesenchymal transition in breast cancer via a novel mechanism, upregulation of GATA-3 expression.

Notch3 and GATA binding protein 3 (GATA-3) have been, individually, shown to maintain luminal phenotype and inhibit epithelial-mesenchymal transition (EMT) in breast cancers. In the present study, we report that Notch3 expression positively correlates with that of GATA-3, and both are associated with estrogen receptor-α (ERα) expression in breast cancer cells. We demonstrate in vitro and in vivo that Notch3 suppressed EMT and breast cancer metastasis by activating GATA-3 transcription. Furthermore, Notch3 knockdown downregulated GATA-3 and promoted EMT; while overexpression of Notch3 intracellular domain upregulated GATA-3 and inhibited EMT, leading to a suppression of metastasis in vivo. Moreover, inhibition or overexpression of GATA-3 partially reversed EMT or mesenchymal-epithelial transition induced by Notch3 alterations. In breast cancer patients, high GATA-3 expression is associated with higher Notch3 expression and lower lymph node metastasis, especially for hormone receptor (HR) positive cancers. Herein, we demonstrate a novel mechanism whereby Notch3 inhibit EMT by transcriptionally upregulating GATA-3 expression, at least in part, leading to the suppression of cancer metastasis in breast cancers. Our findings expand our current knowledge on Notch3 and GATA-3's roles in breast cancer metastasis.

FoxM1 is a promising candidate target in the treatment of breast cancer.

Forkhead box protein M1(FoxM1) is a member of forkhead superfamily transcription factors. Emerging evidences have progressively contributed to our understanding on a central role of FoxM1 in human cancers. However, perspectives on the function of FoxM1 in breast cancer (BC) remain conflicting, and mostly were from basic research. Here, we explored the expression profile and prognostic values of FoxM1 based on analysis of pooled clinical datasets derived from online accessible databases, including ONCOMINE, Breast Cancer Gene-Expression Miner v4.0, and Kaplan-Meier plotter. It was found that, FoxM1 mRNA expression was significantly higher in breast tumor versus normal control. FoxM1expression profile presented a distinct pattern in different molecular subtypes of BC patients. Higher expression of FoxM1 was correlated to low mRNA expression of estrogen receptor 1 (ESR1), erb-B2 receptor tyrosine kinase 2 (ERBB2), and was inversely associated with the expression of classical luminal regulators forkhead box protein A1 (FoxA1) and GATA binding protein 3 (GATA3). Elevated FoxM1 expression predicted shorter distance metastasis free survival (DMFS) in BC patients, particularly with estrogen receptor (ER) positive and Luminal A, Luminal B subtypes of BC. More interestingly, elevated FoxM1 expression predicted poor survival in breast cancer patients, especially in the ER (+), progesterone receptor (PR) (+) subgroups and BC patients received adjuvant chemotherapy only or treated with tamoxifen only. These results implied that FoxM1 is an essential prognostic factor and promising candidate target in the treatment of breast cancer.

Predictive Value of Preoperative Multidetector-Row Computed Tomography for Axillary Lymph Nodes Metastasis in Patients With Breast Cancer.

Introduction: Axillary lymph nodes (ALN) status is an essential component in tumor staging and treatment planning for patients with breast cancer. The aim of present study was to evaluate the predictive value of preoperative multidetector-row computed tomography (MDCT) for ALN metastasis in breast cancer patients. Methods: A total of 148 cases underwent preoperative MDCT examination and ALN surgery were eligible for the study. Logistic regression analysis of MDCT variates was used to estimate independent predictive factors for ALN metastasis. The prediction of ALN metastasis was determined with MDCT variates through receiver operating characteristic (ROC) analysis. Results: Among the 148 cases, 61 (41.2%) cases had ALN metastasis. The cortical thickness in metastatic ALN was significantly thicker than that in non-metastatic ALN (7.5 ± 5.0 mm vs. 2.6 ± 2.8 mm, P < 0.001). Multi-logistic regression analysis indicated that cortical thickness of >3 mm (OR: 12.32, 95% CI: 4.50-33.75, P < 0.001) and non-fatty hilum (OR: 5.38, 95% CI: 1.51-19.19, P = 0.009) were independent predictors for ALN metastasis. The sensitivity, specificity and AUC of MDCT for ALN metastasis prediction based on combined-variated analysis were 85.3%, 87.4%, and 0.893 (95% CI: 0.832-0.938, P < 0.001), respectively. Conclusions: Cortical thickness (>3 mm) and non-fatty hilum of MDCT were independent predictors for ALN metastasis. MDCT is a potent imaging tool for predicting ALN metastasis in breast cancer. Future prospective study on the value of contrast enhanced MDCT in preoperative ALN evaluation is warranted.

Prognostic values of distinct CBX family members in breast cancer.

Chromobox (CBX) family proteins are canonical components in polycomb repressive complexes 1 (PRC1), with epigenetic regulatory function and transcriptionally repressing target genes via chromatin modification. A plethora of studies have highlighted the function specifications among CBX family members in various cancer, including lung cancer, colon cancer and breast cancer. Nevertheless, the functions and prognostic roles of distinct CBX family members in breast cancer (BC) remain elusive. In this study, we reported the prognostic values of CBX family members in patients with BC through analysis of a series of databases, including CCLE, ONCOMINE, Xena Public Data Hubs, and Kaplan-Meier plotter. It was found that the mRNA expression of CBX family members were noticeably higher in BC than normal counterparts. CBX2 was highly expressed in Basal-like and HER-2 subtypes, while CBX4 and CBX7 expressions were enriched in Luminal A and Luminal B subtypes of BC. Survival analysis revealed that CBX1, CBX2 and CBX3 mRNA high expression was correlated to worsen relapse-free survival (RFS) for all BC patients, while CBX4, CBX5, CBX6 and CBX7 high expression was correlated to better RFS in this setting. Noteworthily, CBX1 and CBX2 were associated with chemoresistance whereas CBX7 was associated with tamoxifen sensitivity, as well as chemosensitivity in breast tumors. Therefore, we propose that CBX1, CBX2 and CBX7 are potential targets for BC treatment. The results might be beneficial for better understanding the complexity and heterogeneity in the molecular underpinning of BC, and to develop tools to more accurately predict the prognosis of patients with BC.

Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-α.

The luminal A phenotype is the most common breast cancer subtype and is characterized by estrogen receptor α expression (ERα). Identification of the key regulator that governs the luminal phenotype of breast cancer will clarify the pathogenic mechanism and provide novel therapeutic strategies for this subtype of cancer. ERα signaling pathway sustains the epithelial phenotype and inhibits the epithelial-mesenchymal transition (EMT) of breast cancer. In this study, we demonstrate that Notch3 positively associates with ERα in both breast cancer cell lines and human breast cancer tissues. We found that overexpression of Notch3 intra-cellular domain, a Notch3 active form (N3ICD), in ERα negative breast cancer cells re-activated ERα, while knock-down of Notch3 reduced ERα transcript and proteins, with alteration of down-stream genes, suggesting its ability to regulate ERα. Mechanistically, our results show that Notch3 specifically binds to the CSL binding element of the ERα promoter and activates ERα expression. Moreover, Notch3 suppressed EMT, while suppression of Notch3 promoted EMT in cellular assay. Overexpressing N3ICD in triple-negative breast cancer suppressed tumorigenesis and metastasis in vivo. Conversely, depletion of Notch3 in luminal breast cancer promoted metastasis in vivo. Furthermore, Notch3 transcripts were significantly associated with prolonged relapse-free survival in breast cancer, in particular in ERα positive breast cancer patients. Our observations demonstrate that Notch3 governs the luminal phenotype via trans-activating ERα expression in breast cancer. These findings delineate the role of a Notch3/ERα axis in maintaining the luminal phenotype and inhibiting tumorigenesis and metastasis in breast cancer, providing a novel strategy to re-sensitize ERα negative or low-expressing breast cancers to hormone therapy.

CCR10 activation stimulates the invasion and migration of breast cancer cells through the ERK1/2/MMP-7 signaling pathway.

CCR10, a member of the chemokine receptor subfamily, is overexpressed in several tumors and play a crucial role in cancer development and progression. However, the functions of CCR10 in breast cancer are unknown. Here, we detected the protein levels of CCR10 in breast cancer cells by western blotting, and examined CCR10 expression in breast cancer tissues via immunohistochemical assay. The results showed that CCR10 expression was elevated in breast cancer MCF7, BT-474 and MDA-MB-231 cells. Further, 63 of 89 cases (70.8%) had positive CCR10 staining, and the CCR10 level was closely related to capsular invasion, lymph node metastasis and tumor stage. Moreover, CCL27, the ligand of CCR10, dose-dependently stimulated the invasion and migration of breast cancer cells, and promoted MMP-7 expression and ERK1/2 activation. CCR10 knockdown in breast cancer cells through siRNA transfection attenuated CCL27-induced cell invasiveness, and suppressed MMP-7 expression and ERK1/2 activation. Additionally, blocking the ERK1/2 pathway inhibited the CCL27/CCR10-promoted cell invasion of breast cancer cells. Together, these data suggest that CCL27/CCR10 interaction induces the ERK1/2 pathway, which then increases MMP-7 expresion and subsequently promotes breast cancer cell invasion and migration. Thus, CCR10 may be a key regulator in breast cancer cell invasion and migration.

GATA3 and TRPS1 are distinct biomarkers and prognostic factors in breast cancer: database mining for GATA family members in malignancies.

GATA transcription factors are zinc finger DNA binding proteins that activate transcription during development and cell differentiation. To date, 7 members of GATA family have been reported. However, the expression patterns and the exact roles of distinct GATA family members contributing to tumorigenesis and progression of breast cancer (BC) remain to be elucidated. Here, we studied the expression of GATA transcripts in a variety of tumor types compared with the normal controls using the ONCOMINE and GOBO databases, along with their corresponding expression profiles in an array of cancer cell lines through CCLE analysis. Based on Kaplan-Meier plotter, we further investigated the prognostic values of GATA members specifically high expressed in BC patients. It was found that, when compared with normal tissues, GATA3 and TRPS1 were distinctly high expressed in BC patients among all GATA members. GATA3 expression was significantly associated with ESR1, while TRPS1 was correlated with ERBB2. In survival analysis, GATA3 and TRPS1 mRNA high expressions were correlated to better survival in BC patients, and TRPS1 high expression was significantly associated with longer RFS in patients who have received chemotherapy. These results suggest that GATA3 and TRPS1 are distinct biomarkers and essential prognostic factors for breast cancer.

Notch3 overexpression causes arrest of cell cycle progression by inducing Cdh1 expression in human breast cancer cells.

Uncontrolled cell proliferation, genomic instability and cancer are closely related to the abnormal activation of the cell cycle. Therefore, blocking the cell cycle of cancer cells has become one of the key goals for treating malignancies. Unfortunately, the factors affecting cell cycle progression remain largely unknown. In this study, we have explored the effects of Notch3 on the cell cycle in breast cancer cell lines by 3 methods: overexpressing the intra-cellular domain of Notch3 (N3ICD), knocking-down Notch3 by RNA interference, and using X-ray radiation exposure. The results revealed that overexpression of Notch3 arrested the cell cycle at the G0/G1 phase, and inhibited the proliferation and colony-formation rate in the breast cancer cell line, MDA-MB-231. Furthermore, overexpressing N3ICD upregulated Cdh1 expression and resulted in p27(Kip) accumulation by accelerating Skp2 degradation. Conversely, silencing of Notch3 in the breast cancer cell line, MCF-7, caused a decrease in expression levels of Cdh1 and p27(Kip) at both the protein and mRNA levels, while the expression of Skp2 only increased at the protein level. Correspondingly, there was an increase in the percentage of cells in the G0/G1 phase and an elevated proliferative ability and colony-formation rate, which may be caused by alterations of the Cdh1/Skp2/p27 axis. These results were also supported by exposing MDA-MB-231 cells or MCF-7 treated with siN3 to X-irradiation at various doses. Overall, our data showed that overexpression of N3ICD upregulated the expression of Cdh1 and caused p27(Kip) accumulation by accelerating Skp2 degradation, which in turn led to cell cycle arrest at the G0/G1 phase, in the context of proliferating breast cancer cell lines. These findings help to illuminate the precision therapy targeted to cell cycle progression, required for cancer treatment.

Cytoplasmic Skp2 expression is associated with p-Akt1 and predicts poor prognosis in human breast carcinomas.

BACKGROUND: S-phase kinase protein 2 (Skp2), an oncogenic protein, is a key regulator in different cellular and molecular processes, through ubiquitin-proteasome degradation pathway. Increased levels of Skp2 are observed in various types of cancer and associated with poor prognosis. However, in human breast carcinomas, the underlying mechanism and prognostic significance of cytoplasmic Skp2 is still undefined. METHODS: To investigate the role of cytoplasmic Skp2 expression in human breast carcinomas, we immnohistochemically assessed cytoplasmic Skp2, p-Akt1, and p27 expression in 251 patients with invasive ductal carcinomas of the breast. Association of cytoplasmic Skp2 expression with p-Akt1 and p27 was analyzed as well as correspondence with other clinicopathological parameters. Disease-free survival and overall survival were determined based on the Kaplan-Meier method and Cox regression models. RESULTS: Cytoplasmic of Skp2 was detected in 165 out of 251 (65.7%) patients. Cytoplasmic Skp2 expression was associated with larger tumor size, more advanced histological grade, and positive HER2 expression. Increased cytoplasmic Skp2 expression correlated with p-Akt1 expression, with 54.2% (51/94) of low p-Akt1-expressing breast carcinomas, but 72.6% (114/157) of high p-Akt1-expressing breast carcinomas exhibiting cytoplasmic Skp2 expression. Elevated cytoplasmic Skp2 expression with low p-Akt1 expression was associated with poor disease-free and overall survival (DFS and OS), and Cox regression models demonstrated that cytoplasmic Skp2 expression was an independent prognostic marker for invasive breast carcinomas. CONCLUSION: Cytoplasmic Skp2 expression is associated with aggressive prognostic factors, such as larger tumor size, and advanced histological grade of the breast cancers. Results demonstrate that combined cytoplasmic Skp2 and p-Akt1 expression may be prognostic for patients with invasive breast carcinomas, and cytoplasmic Skp2 may serve as a potential therapeutic target.