Triangular prismatic JJ stent does not cause more discomfort than tubular ones: a randomised controlled trial comparison.

OBJECTIVE: To compare the stent-related symptoms (SRS) of three commonly used, readily accessible ureteric JJ stents after uncomplicated flexible ureteroscopic lithotripsy (FURL), in a prospective randomised controlled single-blind parallel-group study, in order to see whether structural difference might influence SRS. PATIENTS AND METHODS: Patients undergoing FURL were randomised into three groups: the Cook Group received conventional 6 F Cook Universa Soft JJ stents as control, the Kang Yi Bo (KYB) Group received 6 F KYB anti-reflux JJ stents, and the Urovision Group received 7 F Urovision Visiostar ESWL JJ stents. The ureteric stent symptom questionnaire (USSQ) was administered at 1 week, 4 weeks (before stent removal), and 5 weeks (one week after stent removal as baseline evaluation) after stent insertion. Both raw and baseline-adjusted USSQ domain subscores at 1 week and 4 weeks were compared. RESULTS: A total of 146 patients were included in the analysis. The KYB Group showed significantly lower P6&7 subscore yet higher urinary symptoms score 1 week and 4 weeks after stents insertion than both Cook and Urovision, whilst the Urovision Group achieved similar scores in most domains with Cook. CONCLUSIONS: Although the KYB anti-reflux JJ stent might prevent vesicoureteral reflux, it induces significantly stronger urinary symptoms, both at 1 week or 4 weeks after stent insertion, with or without baseline correction. Despite the unique triangular prismatic shape, the Urovision Visiostar stent does not cause heavier urinary symptoms or pain compared to the conventional cylinder shape counterparts.

Correction: Hamilton et al. Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2017, 18, 2305.

In the original publication [...].

Plasma IL-6 and TNF-α levels correlate significantly with grading changes in localized prostate cancer.

PURPOSE: To study the effect of inflammatory markers in blood such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) on the Gleason score (GS) changes in patients with prostate cancer (PCa) after radical prostatectomy (RP), we conducted this study. PATIENTS AND METHODS: From November 2012 to September 2021, a total of 237 patients underwent RP at our institution. Blood samples from all patients were collected within 1 week before surgery. Preoperative clinical characteristics include age, serum IL-6 and TNF-α, neutrophil-to-lymphocyte ratio, C-reactive protein, the platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, the prostate imaging reporting and data system (PI-RADS) score, prostate-specific antigen, and biopsy GS were assessed. Univariate and multivariate logistic regression analyzes were used to determine the risk factors of GS changes after RP. The efficiency of this prediction model was identified with the area under the curve of the receiver operating characteristic curve. RESULTS: Seventy-three patients (30.8%) had GS upgraded in the overall cohort, and 55 patients (23.2%) had GS downgraded. In comparing PCa patients with and without GS upgraded, multivariate logistic regression analysis showed that serum TNF-α (odds ratio [OR]: 2.518, p = 0.019) and IL-6 (OR: 0.478, p = 0.023) were independent factors predicting the occurrence of GS upgrade. We also compared the characteristics of patients with GS upgraded and GS downgraded; multivariate logistic regression analysis also demonstrated significant differences in serum IL-6 and TNF-α between these two groups (all p < 0.05). In addition, we found that low prostate volume and biopsy GS ≥ 7 were significantly associated with higher PI-RADS sores in multivariate analysis. CONCLUSION: The high expression of serum TNF-α level is positively correlated with GS upgraded in PCa patients. High expression of serum IL-6 level is negatively correlated with GS upgraded in PCa patients and positively related with GS downgraded.

Comparison of the effects of extrinsic compression on the drainage performance of three ureteric stents.

OBJECTIVES: To share our centre's experience dealing with ureteric obstruction, in particular malignant obstructions, by investigating the deformation and flow velocity of three commonly used, readily accessible ureteric stents under at different compression levels and surface change at three time points (new, 1 month and 3 months after implantation). SUBJECTS AND METHODS: Scanning electron microscope (SEM) analysis was conducted on ureteric JJ stents, including the Cook Universa Soft, the Kang Yi Bo (KYB) antireflux and the Urovision Visiostar ESWL JJ stents. Deformation caused by compression was measured using a digital force gauge. Intraluminal flow velocity was tested with the stents subject to different compression levels. RESULTS: The Urovision Visiostar JJ stent demonstrated significantly better anti-compression capability. The Cook Universa Soft and KYB antireflux JJ stents showed favourable draining velocity without compression, but the velocity dropped substantially on compression. The velocity of the KYB antireflux JJ stent reduced substantially after 3 months of implantation, while the Urovision Visiostar achieved the best draining effect when under compression at all three time points. CONCLUSION: The Urovision Visiostar JJ stent demonstrated significantly greater resistance to compression than the other two JJ stents, as well as better drainage under compression. Patients with benign or malignant ureteric compression might benefit from use of the Urovision Visiostar stent. Large prospective clinical trials are needed to confirm these findings.

Tumor-Derived Exosomes in Tumor-Induced Immune Suppression.

Exosomes are a class of small membrane-bound extracellular vesicles released by almost all cell types and present in all body fluids. Based on the studies of exosome content and their interactions with recipient cells, exosomes are now thought to mediate "targeted" information transfer. Tumor-derived exosomes (TEX) carry a cargo of molecules different from that of normal cell-derived exosomes. TEX functions to mediate distinct biological effects such as receptor discharge and intercellular cross-talk. The immune system defenses, which may initially restrict tumor progression, are progressively blunted by the broad array of TEX molecules that activate suppressive pathways in different immune cells. Herein, we provide a review of the latest research progress on TEX in the context of tumor-mediated immune suppression and discuss the potential as well as challenges of TEX as a target of immunotherapy.

Emerging roles of the TRPV4 channel in bladder physiology and dysfunction.

The transient receptor potential vanilloid type 4, TRPV4, is a polymodal cation channel which can be activated by diverse stimuli including mechanical, thermal and chemical cues. In the urinary bladder, TRPV4 is not only abundantly expressed in the urothelium but may also be localized in subepithelium, detrusor smooth muscles and afferent neurons. Emerging evidence indicates that the TRPV4 channel plays a sensory role in the uroepithelium, where it may regulate the release of sensory mediators such as ATP, which in turn modulates afferent nerve activity in response to bladder filling during the urination cycle. TRPV4 may also directly regulate detrusor contractility and the urothelial barrier function. Altered TRPV4 expression has been detected in various pathological bladder conditions. As such, TRPV4 may be a promising therapeutic target for bladder dysfunctions.

[Circulating tumor cells in the diagnosis and treatment of early and advanced prostate cancer].

Circulating tumor cells (CTC) are tumor cells that escape from the primary or metastatic tumor into the circulatory system, and closely related to cancer metastasis. Since the samples can be obtained through simple and minimally invasive blood sampling operations, CTCs have a great clinical potential. PCa is one of the most common malignant tumors in men. In recent years, many scholars have conducted studies as to whether CTC technology can be used for the diagnosis and treatment of PCa, as well as for more accurate prediction of the risk of progression. This article summarizes the advances in researches relating CTC technology and the diagnosis and treatment of PCa. CTC detection has been developed from simple counting to phenotypic classification, and even to its combination with the determination of the expressions of specific genes (such as AR, AR-V7, etc.) and single-cell sequencing. Some reports showed that CTC technology has a certain significance in the early diagnosis of PCa, but its main value is demonstrated in drug sensitivity and prognosis evaluation in the late stage of the malignancy. The standardized detection methods and reference values of CTCs in PCa will be important research orientations in the near future.

MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks ER/PR and HER2 receptors. Hence, there is urgency in developing new or novel therapeutic strategies for treatment of TNBC. Our study shows that the Monocyte Chemoattractant Protein-1 (MCP-1) is a marker associated with TNBC and may play a key role in TNBC disease progression. EXPERIMENTAL DESIGN: ELISA method was used to measure secreted MCP-1, and mRNA levels were determined by Real-time PCR in numerous cancer cell lines, representing various breast cancer subtypes. Cellular invasiveness was determined by Boyden chamber assay. RESULTS: Our data show that MCP-1 is upregulated in TNBC cell lines both transcriptionally as well as in secreted protein levels compared to ER-positive luminal cell line, MCF-7. Breast cancer patients, with Basal or Claudin-low subtypes, also showed high expression of MCP-1. MCP-1 treatment induced cell invasion in various breast cancer cell types, without affecting cell proliferation. Small molecule antagonists against Chemokine Receptor 2 (CCR2), cognate receptor for MCP-1 as well as the MAP kinase pathway inhibitor U0126 negatively affected MCP-1 induced MCF-7 cell invasion. This suggests that MCP-1-CCR2 axis may regulate invasiveness via the MAP Kinase pathway. Knocking down MCP-1 decreased cell invasion in TNBC cell line BT-549, along with downregulation of key epithelial to mesenchymal transition markers, N-cadherin and Vimentin. CONCLUSION: Our study suggests that MCP-1 mediated pathways could be potential therapeutic targets for the treatment of TNBC, and could reduce cancer health disparities.

A83-01 inhibits TGF-ß-induced upregulation of Wnt3 and epithelial to mesenchymal transition in HER2-overexpressing breast cancer cells.

PURPOSE: The aim of this study is to investigate the mechanisms of interactions between TGF-ß and Wnt/ß-catenin pathways that induce and regulate EMT and promote breast cancer cells to become resistant to treatment. METHODS: The effect of TGF-ß on Wnt/ß-catenin signaling pathway was examined by using a human Wnt/ß-catenin-regulated cDNA plate array and western blot analysis. The interaction of Twist at promoter of Wnt3 was examined by chromatin immunoprecipitation (ChIP) assay. Secreted Wnt3 level was determined by ELISA assay. RESULTS: HER2-overexpressing breast cancer cells treated with TGF-ß have a reduced response to trastuzumab and exhibited EMT-like phenotype. The TGF-ß-induced EMT in HER2-cells was concordant with upregulation of Wnt3 and ß-catenin pathways. The TGF-ß-induced induction of Wnt3 during EMT was found to be Smad3-dependent. ChIP analysis identified occupancy of Twist at promoter region of Wnt3. Knock-down of Twist by shRNA confirmed the significance of Twist in response to TGF-ß regulating Wnt3 during EMT. Subsequently, TGF-ß-induced matrix metalloproteinases, MMP1, MMP7, MMP9, MMP26, Vascular endothelial growth factors (VEGF), and activation of Wnt/ß-catenin signaling were repressed by the shRNA treatment. TGF-ßR1 ALK5 kinase inhibitor, A83-01 can effectively prevent the TGF-ß-induced Twist and Wnt3. Co-treating A83-01 and trastuzumab inhibited TGF-ß-induced cell invasion significantly in both trastuzumab responsive and resistant cells. CONCLUSIONS: Our data demonstrated an important interdependence between TGF-ß and Wnt/ß-catenin pathways inducing EMT in HER2-overexpressing breast cancer cells. Twist served as a linkage between the two pathways during TGF-ß-induced EMT. A83-01 could inhibit the TGF-ß-initiated pathway interactions and enhance HER2-cells response to trastuzumab treatment.

Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) occurs in 10-15% of all breast cancer patients, yet it accounts for about half of all breast cancer deaths. There is an urgent need to identify new antitumor targets to provide additional treatment options for patients afflicted with this aggressive disease. Preclinical evidence suggests a critical role for insulin-like growth factor-2 (IGF2) and androgen receptor (AR) in regulating TNBC progression. To advance this work, a panel of TNBC cell lines was investigated with all cell lines showing significant expression of IGF2. Treatment with IGF2 stimulated cell proliferation in vitro (p < 0.05). Importantly, combination treatments with IGF1R inhibitors BMS-754807 and NVP-AEW541 elicited significant inhibition of TNBC cell proliferation (p < 0.001). Based on Annexin-V binding assays, BMS-754807, NVP-AEW541 and enzalutamide induced TNBC cell death (p < 0.005). Additionally, combination of enzalutamide with BMS-754807 or NVP-AEW541 exerted significant reductions in TNBC proliferation even in cells with low AR expression (p < 0.001). Notably, NVP-AEW541 and BMS-754807 reduced AR levels in BT549 TNBC cells. These results provide evidence that IGF2 promotes TNBC cell viability and proliferation, while inhibition of IGF1R/IR and AR pathways contribute to blockade of TNBC proliferation and promotion of apoptosis in vitro.

Vitamin D receptor FokI gene polymorphisms may be associated with colorectal cancer among African American and Hispanic participants.

BACKGROUND: Vitamin D plays a role in cancer tumorogenesis and acts through the vitamin D receptor (VDR). Although African Americans have the lowest serum vitamin D levels, supplementation has not yielded a significant improvement in cancer. Gene polymorphisms in VDR may play a role. There is a dearth of information on VDR gene polymorphisms and colorectal cancer (CRC) among under-represented ethnic groups. In this study, the authors examined whether VDR gene single nucleotide polymorphisms (SNPs) were associated with CRC in predominately African American and Hispanic study participants. METHODS: Blood samples were collected from 378 participants, including a group of 78 patients with CRC (cases), a group of 230 noncancer participants without polyps (controls without polyps), and a group of 70 noncancer participants with polyps (controls with polyps). The 4 polymorphic SNPs in VDR (FokI, BsmI, TaqI, and ApaI) were assessed using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: There was a significant association of the VDR-FokI FF genotype with CRC cases (odds ratio, 2.9; P= .036) compared with the controls without polyps. The most common VDR-FokI genotype in the overall study population was the FF genotype (46%). However, upon breakdown by ethnicity, the FF genotype was the most common in African American participants (61%), and the Ff genotype was the most common in Hispanic/Latino participants (49%). When the association was assessed in a multivariate model, there was no significant association with any VDR polymorphism and CRC cases (P> .05). The other 3 polymorphic variants of VDR (BsmI, TaqI, and ApaI) were not associated with CRC. CONCLUSIONS: The results from this study suggest that genetic variation of the VDR-FokI SNPs may influence CRC risk, particularly in African American cohorts.

Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic mice.

BACKGROUND: Data from in vivo and in vitro studies suggest that activation of Akt regulates cell survival signaling and plays a key role in tumorigenesis. Hence, transgenic mice were created to explore the oncogenic role of Akt1 in the development of mammary tumors. METHODS: The transgenic mice were generated by expressing myristoylated-Akt1 (myr-Akt1) under the control of the MMTV-LTR promoter. The carcinogen 7, 12 dimethyl-1,2-benzanthracene (DMBA) was used to induce tumor formation. RESULTS: The MMTV driven myr-Akt1 transgene expression was detected primarily in the mammary glands, uterus, and ovaries. The expression level increased significantly in lactating mice, suggesting that the response was hormone dependent. The total Akt expression level in the mammary gland was also higher in the lactating mice. Interestingly, the expression of MMTVmyr-Akt1 in the ovaries of the transgenic mice caused significant increase in circulating estrogen levels, even at the post-lactation stage. Expression of myr-Akt1 in mammary glands alone did not increase the frequency of tumor formation. However, there was an increased susceptibility of forming mammary tumors induced by DMBA in the transgenic mice, especially in mice post-lactation. Within 34 weeks, DMBA induced mammary tumors in 42.9% of transgenic mice post-lactation, but not in wild-type mice post-lactation. The myr-Akt1 mammary tumors induced by DMBA had increased phosphorylated-Akt1 and showed strong expression of estrogen receptor (ERα) and epidermal growth factor receptor (EGFR). In addition, Cyclin D1 was more frequently up-regulated in mammary tumors from transgenic mice compared to tumors from wild-type mice. Overexpression of Cyclin D1, however, was not completely dependent on activated Akt1. Interestingly, mammary tumors that had metastasized to secondary sites had increased expression of Twist and Slug, but low expression of Cyclin D1. CONCLUSIONS: In summary, the MMTVmyr-Akt1 transgenic mouse model could be useful to study mechanisms of ER-positive breast tumor development.

Urinary ATP may be a biomarker of interstitial cystitis/bladder pain syndrome and its severity.

Urinary tract cells respond to bladder distension by releasing adenosine triphosphate (ATP). Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) exhibit elevated urinary ATP levels compared to asymptomatic controls. This study aimed to evaluate the potential of urinary ATP as a non-invasive biomarker for IC/BPS and its correlation with symptom severity. We included 56 patients diagnosed with IC/BPS and 50 asymptomatic controls. Urine samples were collected from both groups. Urinary ATP levels were quantified using the luciferin-luciferase bioluminescence method. The severity of IC/BPS symptoms was assessed using the visual analogue score (VAS), Interstitial Cystitis Symptom Index (ICSI), and Interstitial Cystitis Problem Index (ICPI) from the O'Leary-Sant score. We specifically examined the correlation between symptom scores and urinary ATP levels in IC/BPS patients. Urinary ATP levels were significantly higher in IC/BPS patients compared to the control group (P < 0.0001). There was a significant positive correlation between urinary ATP concentrations and VAS, ICPI, and ICSI scores among IC/BPS patients (P < 0.0001). The threshold value for ATP concentration was set at 56.6 nM, with an area under the receiver operating characteristic (ROC) curve of 0.811 (95% CI 0.730 - 0.892). Our findings indicate that IC/BPS patients excrete elevated amounts of ATP in their urine. This suggests that urinary ATP might serve as a non-invasive biomarker for IC/BPS, with a predictive potential in terms of symptom severity.

Correction: Wu et al. Expression of MALAT1 Promotes Trastuzumab Resistance in HER2 Overexpressing Breast Cancers. Cancers 2020, 12, 1918.

In the original publication, there was a mistake in Figure 4B as published [...].

Inflammatory Cytokines Associated with Obesity, Type-2 Diabetes, and Hypertension Exacerbate Breast Cancer Risk in Underserved African American and Latin American Women.

Background: Comorbid chronic diseases, such as obesity, Type-2 Diabetes (T2D), and hypertension (HTN), are major public health issues and highly prevalent among underserved African Americans (AA) and Latin Americans (LA). Elevated inflammatory cytokines are underlying processes in comorbidities (obesity, T2D, and HTN) that could contribute to tumorigenesis and adverse cancer outcomes. Methods: A panel of 19 cytokines was measured by Luminex assay from 570 AA and LA women's serum samples. The comorbidities and breast cancer information were extracted from our existing clinical database. Comorbidity-associated cytokines were identified by linear regression analysis, and the odds ratios of increasing cytokines for breast cancer were evaluated by Logistic regression. Results: Women with obesity, T2D, and HTN elevated specific groups of cytokines. EGF, MCP1, MDC, MIP-1b, and Groα were independent of T2D and HTN significantly associated with obesity. TGFß1 and TGFß2 were T2D-associated cytokines, and MIB-1b, TNFα, and VEGFα were HTN-associated cytokines. Among those comorbidity-associated cytokines, CXCL1, CCL4, CXCL10, TNFα, TGFß1, and TGFß2 were also significantly associated with breast cancer diagnosed at age < 50. Two or more comorbidities further increased the levels of Groα, MIP-1b, TNFα, and TGFßs. Conclusions: Comorbidity-associate cytokines could augment the risk of breast cancer for AA and LA women.

The clinical utilization of circulating cell free DNA (CCFDNA) in blood of cancer patients.

Qualitative and quantitative testing of circulating cell free DNA (CCFDNA) can be applied for the management of malignant and benign neoplasms. Detecting circulating DNA in cancer patients may help develop a DNA profile for early stage diagnosis in malignancies. The technical issues of obtaining, using, and analyzing CCFDNA from blood will be discussed.

Local treatment Associated With Prognosis among Men With Metastatic Prostate Cancer: A SEER-Based Study.

INTRODUCTION: In order to identify the impact of local treatment on overall survival (OS) and cancer-specific survival(CSS) in men with mPCa. MATERIALS AND METHODS: Men with mPCa undergoing local treatment by radical prostatectomy (RP), radiotherapy (RT) including beam radiation and brachytherapy or no local treatment identified from Surveillance, Epidemiology, and End Results (SEER) database (2010-2015). To evaluate local therapy impact on OS and CSS in relation to baseline characteristics, univariate and multivariable Cox regression analysis was used to predict the prognostic value of local therapy in OS and CSS. RESULTS: A total of 902 (25.8%) patients received local treatment and 2598 (74.2%) patients did not receive local treatment in this study. The Kaplan-Meier curves showed that there was significant difference in OS between patients underwent local treatment and patients without local treatment (P = .013) but not in CSS (P = .068). While multivariate Cox regression analysis showed that local treatment may not significantly improve OS(P = .724). In subgroup analysis, Among patients with prostate-specific antigent (PSA)<10ng/ml, local treatment could significantly improve OS and CSS (all P < .05). Multivariate Cox regression analysis showed that local treatment could be used as an independent prognostic factor to improve OS in mPCa patients with PSA<10ng/ml (P = .031). Another multivariate Cox regression analysis demonstrated that patients with mPCa undergoing RP had better OS and CSS (all P < .05). CONCLUSIONS: Our results showed that local salvage therapy did not seem to be an independent prognostic factor in all mPCa patients, but we found that local therapy can show a better prognosis in patients with lower PSA levels. Compared with RT, patients who had experienced RP may have better prognosis. We still need prospective research to further study the application value of local treatment in mPCa patients.

Genetic variants in African-American and Hispanic patients with breast cancer.

Breast cancer is a disease with significant health disparity affecting mortality in minority women. The present study examined the genetic makeup of breast cancers in African-American and Hispanic/Latinx patients to determine specific genetic mutations associated with breast cancer in the minority population from South Los Angeles, United States. Whole-exome sequencing was performed on DNA extracted from breast cancer tumor biopsies collected from 13 African-American and 15 Hispanic women and 8 matched-normal samples for each ethnic category. The results were analyzed using Ensemble Variant Effect Predictor and Mutation Significance. Additionally, a comparative analysis with The Cancer Genome Atlas data was provided. Our data revealed somatic mutations in genes such as SET domain containing (lysine methyltransferase) 8, serine protease 1 and AT-rich interaction domain 1B (ARID1B) and known breast cancer genes, such as BRCA1/2, TP53 and the DNA damage response genes across all ethnicities. Additionally, Hispanic patients had BRCA1 associated RING domain 1B (BARD1) variants, while African-American patients had higher numbers of nonsynonymous variants in the RAD51 paralog B (RAD51B), ARID1B and X-ray repair cross complementing 3 (XRCC3) genes. In addition, our patients exhibited mutational signature enrichment that indicated DNA homologous recombination repair deficiencies. Therefore, African-American and Hispanic breast cancer samples showed considerable overlap in breast cancer genetic mutations. However, there are differences in specific genetic variants in TP53, BRCA1/2, BARD1 or ARID1B, which will require further study of their role in tumorigenesis.

CircRAD54L2 promotes triple-negative breast cancer progression by regulating the miR-888 family/PDK1 axis.

BACKGROUND: The long-term prognosis of breast cancer with metastasis remains extremely poor. Genetic alterations in tumor cells result in cellular heterogeneity, promoting cancer cells invasion and colonization in some organs during the metastatic process. CircRNAs are very promising as critical biological markers and precise diagnoses in identifying disease mechanisms and developing new methods for effective treatment. However, the role of aberrant expression of circRNAs in breast cancer progression remains largely unknown. METHODS: RNase R treatment and quantitative RT-PCR (qRT-PCR) were performed for circRNA detection. Transwell chamber assays were used to examine the chemotactic migration and invasion of breast cancer cells. RESULTS: This study identified and characterized the circRAD54L2 originating from exon 1, 2, 3, and 4 of the RAD54L2 gene. Importantly, we found that circRAD54L2, rather than RAD54L2 linear mRNA, was significantly upregulated in breast cancer cell lines. Furthermore, we found that inhibiting circRAD54L2 expression markedly reduced the invasion, metastasis, and proliferation of breast cancer cells via sponging of the miR-888 family, which downregulated the expression of pyruvate dehydrogenase kinase 1 (PDK1). CONCLUSION: Our results showed that circRAD54L2 could regulate PDK1 expression by sponging the miR-888 family competing for the ceRNA mechanism, indicating that circRAD54L2 may act as an essential upstream regulator and providing further mechanistic evidence to support the notion that circRAD54L2/miR-888s/PDK1 is a promising therapeutic target in the treatment of breast cancer.