Jyh-Cherng Yu

Luminal breast cancer is rising rapidly among East Asian women, particularly younger patients, with variable clinical outcome, yet current risk-stratification models inadequately predict early recurrence of under-studied young-onset cases. We hypothesize that the interplay between endogenous mutagenic processes and overlooked environmental carcinogen exposure drives molecular diversity, revealing novel etiologic and therapeutic insights. We performed integrative proteogenomic profiling of 164 prospective, treatment-naïve early-stage Taiwanese breast cancer patients using whole-exome sequencing, transcriptomics, proteomics, and phosphoproteomics. Functional validation in luminal models confirmed therapeutic vulnerabilities and biomarkers, with an independent cohort (n = 270) used to stratify high-risk recurrence patients. Our integrative proteogenomic analysis revealed distinct molecular etiologies and actionable vulnerabilities. For the first time, mutation signature analysis revealed both environmental carcinogen exposure (DBAC) and endogenous APOBEC mutagenesis as key contributors to poor disease-free survival, particularly in younger patients. A high-mutation-burden, immune-evasive subgroup revealed immunoepigenetic vulnerabilities. DBAC-driven tumors exhibited overexpression of ROS-detoxifying enzymes, DNA-damage checkpoint activation, and suppressed DNA repair pathways, supporting an environmental-genomic cooperative mechanism. APOBEC-associated tumors exhibited upregulation of APOBEC3B/3F/3G, steroid hormone biosynthesis enzymes, and downstream oncogenic signaling, forming an immunotherapy-responsive subtype. Proteomic classification further resolved luminal heterogeneity beyond PAM50, identifying two clinically relevant groups: (1) a young DBAC-proteome subset with suppressed DNA-repair machinery and favorable chemotherapy response; and (2) a recurrence-prone subtype characterized by co-activating ER, PI3K-AKT-mTOR, and CDK4/6/9 signaling. Functional validation demonstrated that selective CDK9 inhibition targeting the p-POLR2A-Ser2 axis significantly outperformed CDK4/6 blockade. Furthermore, a companion panel (HDAC2, ALDH1L2, ARF4, SCAMP3) stratified high-risk recurrence patients in an independent cohort, supporting biomarker-guided therapy for aggressive luminal breast cancer. This study uncovers environmental mutagenesis as a previously overlooked but critical driver of luminal breast cancer heterogeneity in East Asian patients. We establish a proteogenomics-transformative scheme to guide risk stratification and subtype-specific vulnerabilities, offering a precision oncology strategy for early-stage East Asian breast cancer management.

We present the case of a 59-year-old Taiwanese female who is married and retired, and was diagnosed with invasive ductal carcinoma in her right breast at stage cT1cN0 (Stage IA). She visited us for further treatment and underwent breast-conserving surgery after communication. During the surgery in the operating room, Patent Blue V was injected to localize the sentinel lymph nodes. At the same time, the patient developed blue-colored urticaria around her whole body skin after the blue dye injection. This rare reaction alerted us to pay attention to the patient’s vital signs and prevent a severe allergic reaction, but her vital signs remained stable throughout the operation process. Although her vital signs were stable when she returned to the nursing ward, the patient required more time to recover, possibly due to her allergic predisposition.

Background. Women of breast cancer with locoregional recurrence is a ‘high risk’ subgroup with respect to systemic recurrence and mortality after mastectomy. It is important to early identify the prognostic factors on survival outcome following locoregional recurrence after mastectomy, especially in low incidence and young age area. Methods. Of 3,364 patients undergoing mastectomy for breast cancer from 2002 to 2020, total 68 patients (2.02%) with the age of 32 to 81 years, had locoregional recurrence as the first event. We analysed prognostic factors on overall and post-relapse survival outcomes, like as age at primary diagnosis, intrinsic molecular subtypes, initial diagnosis stage, prior neoadjuvant chemotherapy, and time to relapse, by Kaplan-Meier Estimate Method and Cox proportional hazards regression models. Statistical significance was accepted at P < 0.05. Results. Of 68 patients with locoregional recurrence, 37 patients are alive and 31 patients died on the end of study. The survival group has longer time to relapse (mean, 77.87 vs. 33.28 months), compared to the mortality group. Among all collected factors, age at primary diagnosis (age ≦ 55 vs. >55 y/o) is one important prognostic factor on overall (p = 0.044) and post-relapse survival outcomes (p = 0.046), after controlled all confounding factors of initial diagnosis stage, prior neoadjuvant chemotherapy condition, and time to relapse after initial therapy by cox proportional hazard model. Conclusions. The patients with the age > 55 years at primary diagnosis is a significantly poor prognostic factor on survival outcome following locoregional recurrence after mastectomy, so they need more aggressive treatment when encountering locoregional recurrence.

Background: Both IGF-1R/PI3K/AKT/mTOR and Hippo pathways are crucial for breast cancer stem cells (BCSCs). However, their interplay remains unclear. Methods: Four triple negative breast cancer cell lines derived from CSC of two patient-derived xenografts (PDXs), AS-B145, AS-B145-1R, AS-B244, and AS-B244-1R, were used to elucidate the role of YAP in BCSCs. YAP silenced BCSCs were analyzed by cell proliferation, aldehyde dehydrogenase (ALDH) activity, mammosphere formation, and tumorigenesis. The effects of modulating IGF-1R and IGF-1 on YAP expression and localization were evaluated. The clinical correlation of YAP and IGF-1R signaling with the overall survival (OS) of 7830 breast cancer patients was analyzed by KM plotter. Results: Knockdown of YAP abates the viability and stemness of BCSCs in vitro and tumorigenicity in vivo. Depletion of IGF-1R by shRNA or specific inhibitor decreases YAP expression. In contrast, IGF-1 addition upregulates YAP and enhances its nuclear localization. YAP overexpression increased the mRNA level of IGF-1, but not IGF-1R. Data mining of clinical breast cancer specimens revealed that basal-like breast cancer patients with higher level of IGF-1 and YAP exhibit significantly shorter OS. Conclusions: YAP contributes to stemness features of breast cancer in vitro and in vivo. The expression and localization of YAP was regulated by IGF-1R and YAP expression in turns upregulates IGF-1, but not IGF-1R. Clinically, higher level of YAP and IGF-1 significantly correlated with shorter OS in basal-like breast cancer. Taken together, these findings suggest the clinical relevance of interplay between YAP and IGF-1/IGF-1R pathway in sustaining the properties of BCSCs.

Total intravenous anesthesia (TIVA) with remifentanil and propofol (RP) is considered to be an ideal type of general anesthesia (GA) for pediatric and adult patients undergoing medical procedures. However, delivery of an RP mixture by target-controlled infusion (TCI) for GA in surgical procedures has not been described. We investigated the merit of this approach for breast cancer surgery. Eighty-four patients (n = 42 per group) were randomly allocated to propofol and remifentanil either delivered by separate TCI pumps (S group) or in an RP mixture by a single TCI pump (M group). Dosages were adjusted based on the bispectral index (BIS) and the analgesia nociception index (ANI). The primary outcomes were adequate anesthesia (BIS 40–60 and ANI 50–70, respectively), acceptable hemodynamic fluctuations (p = 0.005). The total dosage of anesthetics, pain rating, patient satisfaction, need for opioids postoperatively, and incidence of adverse events were not significantly different. We have demonstrated that this RP mixture provided adequate hypnotic and analgesic effects under BIS and ANI monitoring in patients undergoing breast cancer surgery within 1 h.

Elevated expression of C-X-C motif chemokine receptor 4 (CXCR4) correlates with chemotaxis, invasion, and cancer stem cell (CSC) properties within several solid-tumor malignancies. Recent studies reported that microRNA (miRNA) modulates the stemness of embryonic stem cells. We aimed to investigate the role of miRNA, via CXCR4-modulation, on CSC properties in breast cancer using cell lines and xenotransplantation mouse model and evaluated miR-193 levels in 191 patients with invasive ductal carcinoma. We validated miR-139 directly targets the 3′-untranslated region of CXCR4. Hoechst 33342 fluorescence-activated cell sorting (FACS) and sphere-forming assay were used to identify CSCs. MiR-139 suppressed breast CSCs with mesenchymal traits; led to decreased migration and invasion abilities through down-regulating CXCR4/p-Akt signaling. In lung cancer xenograft model of nude mice transplanted with human miR-139-carrying MDA-MB-231 cells, metastatic lung nodules were suppressed. Clinically, microdissected breast tumor tissues showed miR-139 reduction, compared to adjacent non-tumor tissues, that was significantly associated with worse clinicopathological features, including larger tumor size, advanced tumor stage and lymph node metastasis; moreover, reduced miR-139 level was predominately occurred in late-stage HER2-oreexpression tumors. Collectively, our findings highlight miR-139-mediated suppression of CXCR4/p-Akt signaling and thereby affected mesenchymal stem-cell genesis, indicating its potential as a therapeutic target for invasive breast cancer.

Background: To realize the association between stratified expression levels of ER and PgR and long-term prognosis of breast cancer patients who received adjuvant hormone therapy, this study aimed to propose better prognostic cut-off levels for estrogen receptor (ER) and progesterone receptor (PgR). Methods: Patients who received adjuvant hormone therapy after surgical intervention were selected. The ER and PgR status and their effects on breast cancer-specific survival (BCSS) and disease-free survival (DFS) over 5 and 10 years were evaluated. Next, subgroups were generated based on ER and PgR expression percentage and Allred scores. Survival curves were constructed using the Kaplan–Meier method. Results: ER and PgR expression were significantly associated with better prognosis in 5 years, whereas only PgR expression was significantly associated during the 10-year follow-up. The optimal cut-off values for better 5-year BCSS were ER > 50%; ER Allred score > 7; PgR ≥ 1%; or PgR Allred score ≥ 3; the corresponding values for DFS were ER > 40%; ER Allred score > 6; PgR > 10%; or PgR Allred score ≥ 3. In the long-term follow-up, PgR of > 50% or Allred score of > 5 carriers revealed a better prognosis of both BCSS and DFS. Conclusion: Patients with a PgR expression > 50% or an Allred score > 5 exhibited better 10-year BCSS and DFS.

Most genome‐wide association studies (GWASs) identify genetic variants for breast cancer occurrence. In contrast, few are for recurrence and mortality. We conducted a GWAS on breast cancer survival after diagnosis in estrogen receptor‐positive patients, including 953 Taiwanese patients with 159 events. Through Cox proportional hazard models estimation, we identified 24 risk SNPs with p < 1 × 10⁻⁵. Based on imputation and integrated analysis, one SNP, rs1024176 (located in 1q24.2, p = 2.43 × 10⁻⁵) was found to be a functional variant associated with breast cancer survival and XCL1 gene expression. A series of experimental approaches, including cell‐based analyses and CRISPR/Cas9 genome‐editing system, were then used and identified the transcription factor MYBL2 was able to discriminately bind to the A allele of rs1024176, the protective variant for breast cancer survival, which promoted XCL1 expression, but not to the G allele of rs1024176. The chemokine XCL1 attracts type 1 dendritic cells (DC1s) to the tumor microenvironment. In breast cancer tissues, we applied a two‐step Mendelian randomization analysis, using expression quantitative trait loci as instrumental variables, to confirm higher XCL1 expression was correlated with higher DC1 signatures and favorable disease progression, through the causal effect of rs1024176‐A allele. Our study supports the genetic effect on preventing breast cancer survival through XCL1‐induced DC1 recruitment in tumor microenvironment.

Current prognostic tools and targeted therapeutic approaches have limited value for metastatic triple negative breast cancer (TNBC). Building upon current knowledge, we hypothesized that epoxyeicosatrienoic acids (EETs) and related CYP450 epoxygenases may have differential roles in breast cancer signaling, and better understanding of which may uncover potential directions for molecular stratification and personalized therapy for TNBC patients. We analyzed the oxylipin metabolome of paired tumors and adjacent normal mammary tissues from patients with pathologically confirmed breast cancer (N = 62). We used multivariate statistical analysis to identify important metabolite contributors and to determine the predictive power of tumor tissue metabolite clustering. In vitro functional assays using a panel of breast cancer cell lines were carried out to further confirm the crucial roles of endogenous and exogenous EETs in the metastasis transformation of TNBC cells. Deregulation of associated downstream signaling networks associated with EETs/CYPs was established using transcriptomics datasets from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Comparative TNBC proteomics using the same tissue specimens subjected to oxylipin metabolomics analysis was used as validation set. Metabolite-by-metabolite comparison, tumor immunoreactivity, and gene expression analyses showed that CYP epoxygenases and arachidonic acid-epoxygenation products, EET metabolites, are strongly associated with TNBC metastasis. Notably, all the 4 EET isomers (5,6-, 8,9-, 11,12-, and 14,15-EET) was observed to profoundly drive the metastasis transformation of mesenchymal-like TNBC cells among the TNBC (basal- and mesenchymal-like), HER2-overexpressing and luminal breast cancer cell lines examined. Our pathway analysis revealed that, in hormone-positive breast cancer subtype, CYP epoxygenase overexpression is more related to immune cell-associated signaling, while EET-mediated Myc, Ras, MAPK, EGFR, HIF-1α, and NOD1/2 signaling are the molecular vulnerabilities of metastatic CYP epoxygenase-overexpressing TNBC tumors. This study suggests that categorizing breast tumors according to their EET metabolite ratio classifiers and CYP epoxygenase profiles may be useful for prognostic and therapeutic assessment. Modulation of CYP epoxygenase and EET-mediated signaling networks may offer an effective approach for personalized treatment of breast cancer, and may be an effective intervention option for metastatic TNBC patients.

Introduction: Ingestion of a foreign body rarely results in perforation of the gastrointestinal tract. Foreign bodies such as dentures, fish bones, chicken bones, toothpicks and cocktail sticks have been known to cause bowel perforation; however, bowel perforation caused by shrimp leg has not been reported so far. Presentation of case: We report a case of a 69-years-old man who presented with a 4-months epigastric pain. Laboratory data revealed inflammation at the first hospital visit. Computed tomography revealed a hypodense lesion containing a hyperdense foreign body in the abdomen. Intra-abdominal abscess caused by foreign body perforation was diagnosed. Discussion: An increased incidence of perforation has been reported in association with Meckel's diverticulum, the appendix, and diverticular disease. The abdominal abscess in this case was located beside the diverticulum of transverse colon, so the perforation most likely occurred in the diverticulum of transverse colon. Conclusion: Perforation of colon by shrimp leg is very rare and not reported currently. Although some cases have been successfully treated chronic foreign-body perforation with abscess by using antibiotics alone, typical treatments remains surgical drainage of the abscess and removal of foreign body. Highlights: