Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a five-year survival rate below 12%, primarily due to rapid development of chemoresistance. To identify molecular drivers of drug resistance, we performed integrated transcriptomic, proteomic, and methylation analyses on gemcitabine-resistant PANC-1 GR cells. We identified the methyltransferase-like protein METTL7B as a novel regulator of RNA methylation-mediated resistance in PDAC. Global m6A profiling revealed hypermethylation in resistant cells that correlated with elevated METTL7B expression. Analysis of TCGA and UALCAN datasets confirmed METTL7B upregulation in PDAC tissues, particularly in KRAS-mutant tumors, and its association with poor overall and disease-free survival. Functional assays demonstrated that METTL7B knockdown suppressed proliferation, migration, invasion, and colony formation while restoring gemcitabine sensitivity. Mechanistically, m6A-seq and RNA-seq analyses revealed that METTL7B methylates oncogenic transcripts such as CSF2, CDKN1A, and FoxM1, enhancing their mRNA stability and translation to promote cell-cycle progression and stress adaptation. Network and pathway analyses further linked METTL7B activity to activation of KRAS and STAT3 signaling, indicating its role in PDAC aggressiveness. Collectively, these results identify METTL7B as a key epitranscriptomic regulator of gemcitabine resistance through m6A-dependent stabilization of oncogenic mRNAs and activation of pro-survival pathways. Targeting METTL7B-mediated RNA methylation offers a promising therapeutic strategy to overcome chemoresistance and improve clinical outcomes in PDAC. Citation Format: Tung-Wei Hsu, Wan-Yu Wang, Yen-Hao Su, Chih-Ming Su, Po-Chen Tseng, Hsin-An Chen. METTL7B-driven m6A RNA methylation promotes gemcitabine resistance and tumor progression in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3121.

BACKGROUND:Lactate dehydrogenase A (LDHA) can regulate tumorigenesis and cancer progression. Nevertheless, whether the regulation of LDHA is involved in the development of gemcitabine resistance in PDAC has not yet been fully elucidated. Increasing studies have shown that cancer acquired drug resistance led to treatment failure is highly attributed to the cancer stem cell (CSC) properties. Therefore, we aim to demonstrate the functions and regulatory mechanisms of LDHA on cancer stem cell (CSC) properties and gemcitabine resistance in PDAC. METHODS:We investigate the metabolite profiles by liquid chromatography-mass spectrometry between gemcitabine-resistant PDAC and parental PDAC cells. Additionally, gain-of-function and loss-of-function experiments were conducted to examine the roles of LDHA on CSC properties and gemcitabine resistance in the gemcitabine-resistant PDAC and parental PDAC cells. To investigate regulators involved in LDHA-mediated gemcitabine resistance and CSC of pancreatic cancer cells, we further used a combination of the miRNA microarray results and software predictions and confirmed that miR-4259 is a direct target of LDHA by luciferase assay. Furthermore, we constructed serial miR-4259 promoter reporters and searched for response elements using the TESS 2.0/TFSEARCH software to find the transcription factor binding site in the promoter region of miR-4259. RESULTS:We observed that elevated LDHA expression significantly correlates with recurrent pancreatic cancer patients following gemcitabine treatment and with CSC properties. We further identify that FOXO3a-induced miR-4259 directly targets the 3'untranslated region of LDHA and reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancer. CONCLUSION:Our results demonstrated that LDHA plays a critical role in cancer stemness and gemcitabine resistance of pancreatic cancer, and indicate that targeting the FOXO3a/miR-4259/LDHA pathway might serve as a new treatment for pancreatic cancer patients with a poor response to gemcitabine chemotherapy.

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths in women worldwide. Approximately 20–30

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second leading cause of cancer-related mortality. Prognostic prediction in HCC is complicated by its heterogeneity, and current treatment strategies are limited to surgical resection and targeted therapies. Sorafenib, a multi-kinase inhibitor and the first-line systemic therapy for advanced HCC, offers modest survival benefits and often induces resistance during long-term administration. Therefore, elucidating the molecular mechanisms of drug resistance is critical for improving therapeutic outcomes. Triptolide is a diterpenoid triepoxide extracted from the traditional Chinese herb Tripterygium wilfordii, exhibits potent anti-inflammatory and anti-neoplastic properties in various cancer types. CARMA3 (CARD10), a membrane-associated scaffold protein, has recently emerged as a key oncogenic regulator in solid tumors. This study demonstrates that CARMA3 contributes to chemoresistance in HCC and that triptolide enhances chemosensitivity by downregulating CARMA3 expression and promoting reactive oxygen species (ROS) accumulation. Our findings suggest that triptolide functions as a chemosensitizing agent by modulating CARMA3-mediated ROS accumulation and ferroptosis resistance, offering a novel therapeutic strategy for overcoming HCC drug resistance.

Abstract Purpose Hormone receptor-positive type of breast cancer is typically treated with hormone therapy (HT), including tamoxifen and aromatase inhibitors (AI). However, long-term use of HT may increase the risks of endometrial cancer, vaginal dryness, and osteoporosis. To minimize the risks, breast surgeons should schedule regular follow-up with gynecologists and arrange bone mass density (BMD) examination. Using the Plan-Do-Study-Act (PDSA) methodology, we aimed to increase cross-team care with gynecology department and to promote BMD examination for breast cancer patients receiving HT. Methods We formed a multidisciplinary team including breast surgery department and gynecologic department in our hospital that care for female patients with breast cancer and related side effects. We arranged a lecture for all collaborative doctors, introducing our aims, interventions, and measurement strategies to test in multiple PDSA cycles. The interventions with standardized criteria include: (1) a gynecologic consultation, triggered if a patient initially receive tamoxifen and (2) a BMD examination, triggered if a patient initially receive AI. The triggering mechanism is embedded in the ambulatory alarming system. Both the intervention rates were tracked during PDSA cycle 1 in 2023 and compared with baseline rates in 2020-2022. Adherence to the plan was maintained and measured using data analytic reports and chart audits. Results The gynecologic consultation rate during PDSA cycle 1 is significantly higher than the baseline, which is 40.4% and 22.4% (p = 0.006), respectively. In patients who received tamoxifen, 6-month-consultation rate during PDSA cycle 1 is also significantly higher than the baseline group, which is 77.77% and 42.9% (p = 0.005), respectively. The median time from HT therapy to first gynecologic consultation decreased from 51 days to 28 days. Furthermore, the baseline BMD testing rate before our intervention was 30.6%. This increased to 48.3% during PDSA cycle 1. Conclusion Standardized gynecologic consultation criteria led to earlier gynecologic consultation in breast cancer patients receiving tamoxifen and higher BMD test rates in patients receiving AI. Future PDSA cycles will focus on assessing the frequency of subsequent gynecologic encounters in patients who received a triggered gynecologic consult. Citation Format: Chiu Ching-Wen, Tam Ka-Wai, Su Chih-Ming, Wu Hsueh-Chi. Building a standard methodology: Early Gynecologic Consultation and Bone Mass Density Examination in Breast Cancer Patients Receiving Endocrine Therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-10-08.

Background and ObjectivesIndication for sentinel lymph node (SLN) biopsy in ductal carcinoma in situ (DCIS) patients with high-upstaging risk remains inconsistent. Our previous systematic review and meta-analysis had reported five variables that were significantly higher in the upstaging group. We developed the "high-risk upstaging model" and investigated its predictivity and accuracy.MethodsThe study included patients initially diagnosed with DCIS in a medical center between 2011 and 2020. Patients' clinicopathological data were obtained through web-based surgical medical record database. Two prediction models were built, in which patients who met at least one (Model A) or two (Model B) of the predictors would be predicted to upstage in the final pathology. We compared the accuracy of our models with National Comprehensive Cancer Network (NCCN) guideline and original data.ResultsThe analyses included 249 patients, of which 67 DCIS patients upstaged in final pathology. The excess treatment in Model A (70%) was lower than the original data (80.2%). The incomplete treatment in Model A (3%) was lower than the NCCN guideline model (38.8%) and the original data (7.5%). Both Model A and Model B yielded a higher receiver operating characteristic (AUC) curve compared with original data.ConclusionsOur Model A derived from the systematic review of the real-world data reduced the incomplete treatment rate of SLNB. Our Model B also showed the highest predictive value. With the two models, we provided a clearer indication for surgeons to perform SLNB in DCIS patients and demonstrated proof of concept, allowing ready input of patient data.

Pancreatic cancer has one of the highest fatality rates and the poorest prognosis among all cancer types worldwide. Gemcitabine is a commonly used first-line therapeutic drug for pancreatic cancer; however, the rapid development of resistance to gemcitabine treatment has been observed in numerous patients with pancreatic cancer, and this phenomenon limits the survival benefit of gemcitabine. Adenylosuccinate lyase (ADSL) is a crucial enzyme that serves dual functions in de novo purine biosynthesis, and it has been demonstrated to be associated with clinical aggressiveness, prognosis, and worse patient survival for various cancer types. In the present study, we observed significantly lower ADSL levels in gemcitabine-resistant cells (PANC-1/GemR) than in parental PANC-1 cells, and the knockdown of ADSL significantly increased the gemcitabine resistance of parental PANC-1 cells. We further demonstrated that ADSL repressed the expression of CARD-recruited membrane-associated protein 3 (Carma3), which led to increased gemcitabine resistance, and that nuclear factor erythroid 2-related factor 2 (Nrf2) regulated ADSL expression in parental PANC-1 cells. These results indicate that ADSL is a candidate therapeutic target for pancreatic cancer involving gemcitabine resistance and suggest that the Nrf2/ADSL/Carma3 pathway has therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Breast cancer is a leading cause of cancer mortality in women worldwide. Using the Infinium MethylationEPIC BeadChip, we analyzed plasma sample methylation to identify the SRCIN1 gene in breast cancer patients. We assessed SRCIN1-related roles and pathways for their biomarker potential. To verify the methylation status, quantitative methylation-specific PCR (qMSP) was performed on genomic DNA and circulating cell-free DNA samples, and mRNA expression analysis was performed using RT‒qPCR. The results were validated in a Western population; for this analysis, the samples included plasma samples from breast cancer patients from the USA and from The Cancer Genome Atlas (TCGA) cohort. To study the SRCIN1 pathway, we conducted cell viability assays, gene manipulation and RNA sequencing. SRCIN1 hypermethylation was identified in 61.8% of breast cancer tissues from Taiwanese patients, exhibiting specificity to this malignancy. Furthermore, its presence correlated significantly with unfavorable 5-year overall survival outcomes. The levels of methylated SRCIN1 in the blood of patients from Taiwan and the USA correlated with the stage of breast cancer. The proportion of patients with high methylation levels increased from 0% in healthy individuals to 63.6% in Stage 0, 80% in Stage I and 82.6% in Stage II, with a sensitivity of 78.5%, an accuracy of 90.3% and a specificity of 100%. SRCIN1 hypermethylation was significantly correlated with increased SRCIN1 mRNA expression (p < 0.001). Knockdown of SRCIN1 decreased the viability of breast cancer cells. SRCIN1 silencing resulted in the downregulation of ESR1, BCL2 and various cyclin protein expressions. SRCIN1 hypermethylation in the blood may serve as a noninvasive biomarker, facilitating early detection and prognosis evaluation, and SRCIN1-targeted therapies could be used in combination regimens for breast cancer patients.

Introduction: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. Currently, patients who respond to neoadjuvant chemotherapy (NAC) are treated with mastectomy and axillary lymph node dissection. This study aimed to synthesize real-world data to evaluate the feasibility of breast-conserving therapy (BCT), sentinel lymph node (SLN), and sentinel lymph node biopsy (SLNB) for patients with IBC who respond to NAC. Methods: PubMed, Embase, and Cochrane Library databases were searched for relevant articles. Clinical studies that compared mastectomy with BCT for IBC treatment were reviewed. The primary outcomes were local recurrence rate and 5-y survival rate in patients with IBC who responded to NAC. Furthermore, the SLN detection rate and false negative rate (FNR) for SLNB were also evaluated. Results: In the final analysis, 17 studies were included. The pooled estimates of the local recurrence rate for mastectomy and no surgical intervention were 18.6% and 15.9%, respectively (P 1/4 0.956). Five-y survival was similar for mastectomy, partial mastectomy, and no surgical intervention (45.8%, 57.1%, and 39.4%, respectively). The pooled estimates of the SLN detection rate and FNR for SLNB were 81.9% and 21.8%, respectively. Conclusions: Among patients with IBC who respond to NAC, the local recurrence and 5-y survival rates in those undergoing BCT are noninferior to the rates in those undergoing mastectomy; therefore, BCT could be a feasible option for surgical management. However, a poor SLN detection rate and a high FNR were found in patients undergoing SLNB. Further large-scale clinical studies are required to confirm our findings. (c) 2023 Elsevier Inc. All rights reserved.

Metastasis in breast cancer usually lead to the majority of deaths on clinical patients. Accordingly, diagnosis of metastasis at the early stage in breast cancer is important to improve the prognosis. We observed that Dicer protein levels are significant decrease in highly invasive breast cancer cells and usually correlated with poor clinical outcomes. Following, we aim to clarify the molecular regulatory mechanism of this phenomenon in breast cancer to provide a new therapeutic target. In this study, we obtained that Dicer expression correlated with metastasis and invasion without affect cell stability in breast cancer cells. Importantly, we identified the regulatory mechanism of Dicer protein degradation, the chaperone-mediated autophagy (CMA)-mediated degradation that is major mechanism to decrease Dicer protein expression and lead to cancer metastasis. We discovered that heat shock cognate 71-kDa protein (Hsc70) which as a CMA-related factor interacts with the CMA-targeting motif I333A/K334A on Dicer to promote degradation through CMA. Taken together, our findings hint that Dicer highly correlated with cancer metastasis, we reveal the tumor-promoting effect of CMA-mediated Dicer degradation in breast cancer.

Purpose: Although ductal carcinoma in situ (DCIS) seldom involves lymph nodes, some patients may upstage to invasive disease, thus requiring a second surgery for sentinel lymph node (SLN) biopsy (SLNB). However, the indications of SLNB remain inconclusive and clinical trials are rarely available. Our aim is to systematically review the real-world data to evaluate whether SLNB is precisely applied in patients with a high risk of upstaging from DCIS to invasive carcinoma.Methods: PubMed, EMBASE, and Cochrane library databases were searched. Prospective and retrospective cohort studies that evaluated the pathological outcomes of SLNB and the upstaging rate in women with DCIS were included. The primary outcomes were the upstaging and SLN-positive rates of patients initially diagnosed as having DCIS. We analyzed factors, namely biopsy methods, clinical presentations, histological patterns, and hormone receptor status, that potentially indicate nodal involvement risk.Results: We retrieved 43 prospective and 69 retrospective studies including 44,001 patients. The pooled estimates of upstaging and SLN-positive rates were 25.8% (95% confidence interval [CI]: 0.230-0.286) and 4.9% (95% CI: 0.042-0.055), respectively. In subgroup analysis, the upstaging rate was significantly higher in patients with estrogen receptor-negative status, palpable mass, tumor size >2 cm on imaging, and high-nuclear grade and those who received a preoperative diagnosis through core needle biopsy.Conclusion: The upstaging and SLN-positive rates of DCIS were 25.8% and 4.9%, respectively. By selecting pa-tients with high risk DCIS, surgeons may increase the precision of and reduce the excess and incomplete treat-ment rates of SLNB.

Background Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression. Methods Circulating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and disease progression. The Cancer Genome Atlas (TCGA) data in Western countries and Illumina methylation arrays in Taiwanese breast cancer patients were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific PCR (QMSP), real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation and mRNA and protein expression levels in 394 samples from Taiwanese and Korean breast cancer patients. TMEM240 gene manipulation, viability, migration assays, RNA-seq, and MetaCore were performed to determine its biological functions and relationship to hormone drug treatment response in breast cancer cells. Results Aberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and migration and regulates the expression levels of enzymes involved in estrone and estradiol metabolism. TMEM240 protein expression was observed in normal breast tissues but was not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least twofold higher in tumor tissues than in matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival (p = 0.003) and poor treatment response, especially hormone therapy response (p < 0.001). Circulating methylated TMEM240 dramatically and gradually decreased and then diminished in patients without disease progression, whereas it returned and its levels in plasma rose again in patients with disease progression. Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy. Conclusions Hypermethylation of TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer.

Background Despite therapeutic advancements, metastasis remains a major cause in breast cancer-specific mortality. Breast cancer cells are susceptible to oxidative damage and exhibit high levels of oxidative stress, including protein damage, DNA damage, and lipid peroxidation. Some breast cancer risk factors may change the level of endogenous oxidative stress. Circulating exosomes play critical roles in tumorigenesis, distant metastasis, and poor prognosis in patients with breast cancer. Methods We used an online database to analyze the expression and prognostic value of core binding factor subunit β (CBFB) and oxidative stress–related targets in patients with breast cancer. Serum from healthy controls and patients with primary breast cancer or bone metastatic breast cancer in the bone was collected. Exosomes were isolated from the sera or cell culture media. We used an MDA-MB-436-innoculated tumor xenograft mouse model for silencing CBFB. Results Circulating exosomes from patients with breast cancer metastasis to the bone were rich in CBFB. The human mammary fibroblast cells HMF3A and fibroblasts derived from patient samples cocultured with exosomes had increased α-SMA and vimentin expression and IL-6 and OPN secretion. Similarly, nonmetastatic breast cancer cells cocultured with exosomes exhibited increased levels of certain markers, including vimentin, snail1, CXCR4, and Runx2, and the exosomes had high CBFB expression. Silencing CBFB in metastatic MDA-MB-436 and MDA-MB-157 cells resulted in suppressed migration and invasion and downregulation of vimentin, CXCR4, snail1, Runx2, CD44, and OPN. Conversely, CBFB overexpression resulted in upregulation of Runx2, vimentin, snail1, CD44, and OPN in nonmetastatic T47D and MCF12A cells. The CBFB-rich exosomes derived from MDA-MB-436 cells induced enhanced metastatic phenotypes in the low-metastatic T47D and MCF12A cell lines. Conclusion Our results revealed that CBFB may promote bone metastasis in patients with breast cancer. Of therapeutic relevance, targeting CBFB resulted in decreased tumor burden and bone metastasis, downregulation of bone metastasis markers, and impaired regulation of oxidative stress–related proteins NAE1 and NOS1.

Epigenetic alterations play a pivotal role in cancer treatment outcomes. Using the methylation array data and The Cancer Genome Atlas (TCGA) dataset, we observed the hypomethylation and upregulation of thiosulfate sulfurtransferase-like domain containing 1 (TSTD1) in patients with breast cancer. We examined paired tissues from Taiwanese patients and observed that 65.09% and 68.25% of patients exhibited TSTD1 hypomethylation and overexpression, respectively. A significant correlation was found between TSTD1 hypomethylation and overexpression in Taiwanese (74.2%, p = 0.040) and Western (88.0%, p < 0.001) cohorts. High expression of TSTD1 protein was observed in 68.8% of Taiwanese and Korean breast cancer patients. Overexpression of TSTD1 in tumors of breast cancer patients was significantly associated with poor 5-year overall survival (p = 0.021) and poor chemotherapy response (p = 0.008). T47D cells treated with TSTD1 siRNA exhibited lower proliferation than the control group, and transfection of TSTD1 in MDA-MB-231 induced the growth of MDA-MB-231 cells compared to the vector control. Additionally, overexpression of TSTD1 in MCF7 cells mediated a poor response to chemotherapy by epirubicin (p < 0.001) and docetaxel (p < 0.001) and hormone therapy by tamoxifen (p =0.025). Circulating cell-free hypomethylated TSTD1 was detected in plasma of Taiwanese breast cancer patients with disease progression and poor chemotherapy efficacy. Our results indicate that promoter hypomethylation and overexpression of TSTD1 in patients with breast cancer are potential biomarkers for poor 5-year overall survival and poor treatment response.

Patients with breast cancer encounter difficulties in making surgical treatment decisions. Shared decision-making (SDM) with patient decision aids (PDAs) can minimize patients’ decisional conflicts. However, the effect of PDAs in Asia remains inconclusive. This study investigated the effect of SDM assisted by PDAs on the decisional conflict of patients with breast cancer. In this two-group, outcome assessor-blind, randomized controlled trial, 151 patients diagnosed as having breast cancer were assigned to the PDA (SDM with PDA) group or the standard (SDM without PDA) group. Demographic and clinical variables were analyzed to identify variables affecting the treatment choice. The patients’ decision-making difficulties were evaluated using the four-item SURE scale during preoperative hospitalization, and decisional conflicts were examined using the five-item Decision Regret scale and Hospital Anxiety and Depression Scale (HADS) 1 month after surgery. The choice of breast conservation therapy and mastectomy did not significantly differ between the PDA and standard groups. The PDA group had a higher level of depression after making decisions (P = 0.029) than did the standard group. No significant difference in the total scores of the SURE scale and Decision Regret scale were noted between the groups. PDAs did not assist the patients with breast cancer in making breast surgery-related decisions. Clinicians should focus on SDM grounded in evidence-based medicine with care and help patients consider their individual preferences. ClinicalTrial.gov, NCT03105076; April 7, 2017 ( http://www.clinicaltrials.gov ).

The early detection of cancer can reduce cancer-related mortality. There is no clinically useful noninvasive biomarker for early detection of breast cancer. The aim of this study was to develop accurate and precise early detection biomarkers and a dynamic monitoring system following treatment. We analyzed a genome-wide methylation array in Taiwanese and The Cancer Genome Atlas (TCGA) breast cancer (BC) patients. Most breast cancer-specific circulating methylated CCDC181, GCM2 and ITPRIPL1 biomarkers were found in the plasma. An automatic analysis process of methylated ccfDNA was established. A combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was performed in R using Recursive Partitioning and Regression Trees to establish a new prediction model. Combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was found to have a sensitivity level of 97% and an area under the curve (AUC) of 0.955 in the training set, and a sensitivity level of 100% and an AUC of 0.961 in the test set. The circulating methylated CCDC181, GCM2 and ITPRIPL1 was also significantly decreased after surgery (all p < 0.001). The aberrant methylation patterns of the CCDC181, GCM2 and ITPRIPL1 genes means that they are potential biomarkers for the detection of early BC and can be combined with breast imaging data to achieve higher accuracy, sensitivity and specificity, facilitating breast cancer detection. They may also be applied to monitor the surgical treatment response.

Gemcitabine has been a commonly used therapeutic agent for treatment of pancreatic cancer. In the clinic, a growing resistance to gemcitabine has been observed in patients with pancreatic cancer, and investigation of the underlying mechanism of gemcitabine resistance is urgently required. The microRNA (miRNA)‐producing enzyme, Dicer, is crucial for the maturation of miRNAs, and is involved in clinical aggressiveness, poor prognosis, and survival outcomes in various cancers, however, the role of Dicer in acquired gemcitabine resistance of pancreatic cancer is still not clear. Here, we found that Dicer expression was significantly increased in gemcitabine‐resistant PANC‐1 (PANC‐1/GEM) cells compared with parental PANC‐1 cells and observed a high level of Dicer correlated with increased risk of pancreatic cancer. Suppression of Dicer obviously decreased gemcitabine resistance in PANC‐1/GEM cells; consistently, overexpression of Dicer in PANC‐1 cells increased gemcitabine resistance. Moreover, we identified that transcriptional factor Sp1 targeted the promoter region of Dicer and found ERK/Sp1 signaling regulated Dicer expression in PANC‐1/GEM cells, as well as positively correlated with pancreatic cancer progression and suggest that targeting the ERK/Sp1/Dicer pathway has potential therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Background: Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression. Methods: Circulating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and relapse events. Illumina methylation arrays were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific real-time polymerase chain reaction (QMSP), quantitative real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation, mRNA and protein expression levels in 335 breast samples from Taiwanese and Korean patients. Kaplan–Meier curves, Cox proportional hazards regression and receiver operating characteristic curves were used to analyze 10-year survival and disease progression. The Cancer Genome Atlas (TCGA) dataset was used to investigate TMEM240 alterations in Western countries. Transient transfection and knockdown of TMEM240 were performed to determine its biological functions and its relationship to hormone drug treatment response in breast cancer cells. Results: Aberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and cell migration. TMEM240 protein expression was observed in normal breast tissues, but not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. Almost all triple-negative breast cancer patients (95.7%, 22/23) had deficient TMEM240 protein expression. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least 2-fold higher in tumor tissues than in the matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival ( p = 0.003) and poor treatment response, especially hormone therapy response ( p < 0.001). Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy, better than the currently used biomarkers CEA and CA-153. Conclusions: Circulating methylated TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer.