A retrospective cohort study of tamoxifen versus surgical treatment for ER-positive gynecomastia.

BACKGROUND: Gynecomastia is a common condition in clinical practice. The present study aimed to review the clinical data of ER-positive gynecomastia patients treated by tamoxifen (TAM) versus surgery and discussed the clinical effects of the two treatment strategies. METHOD: We retrospectively collected the clinical indicators of patients with unilateral or bilateral gynecomastia who received treatment at our hospital between April 2018 and December 2021. Depending on the treatment received, the patients were divided into TAM and surgery groups. RESULT: A total of 170 patients were recruited, including 91 patients in TAM group and 79 patients in surgery group. The age of the patients differed significantly between the TAM and surgery groups (P < 0.01). The estrogen level was closer in patients with stable and progressive disease, but significantly different in patients of glandular shrinkage in TAM group (P < 0.01). The proportion of patients achieving stable disease was higher among those with clinical grade 1-2. Among patients classified as clinical grade 3, the proportion of patients achieving glandular shrinkage of the breast was higher after TAM treatment (P < 0.05). The age and length of hospital stay were significantly different in patients undergoing open surgery than minimally invasive rotary cutting surgery and mammoscopic-assisted glandular resection (P < 0.01). Patients had significantly different complications including mild postoperative pain, hematoma, nipple necrosis, nipple paresthesias and effusions among the surgery subgroups (all P < 0.05). The estrogen level and the type of surgery were significantly different between the surgical recurrence and non-recurrence subgroups (P < 0.05). The difference in the thickness of glandular tissues upon the color Doppler ultrasound also reached a statistical significance between the two groups (P = 0.050). An elevated estrogen level was a factor leading to TAM failure. Among surgical patients, the thickness of glandular tissues, estrogen level, and type of surgery performed were risk factors for postoperative recurrence (all P < 0.05). CONCLUSION: Both treatment strategies can effectively treat gynecomastia, but different treatment methods can benefit different patients. TAM treatment is more beneficial than surgery for patients who cannot tolerate surgery, have a low estrogen level, and are clinical grade 1-2. Surgery treatment is better than TAM for patients of clinical grade 3. Different surgery options may lead to different complications. Patients with a greater glandular tissue thickness and a higher estrogen level were shown to have a higher risk of recurrence.

Oncological outcome of complete response after neoadjuvant chemotherapy for breast conserving surgery: a systematic review and meta-analysis.

BACKGROUND: With limited sample sizes and single-institution designs, how complete response (CR) after neoadjuvant chemotherapy (NAC) influences breast conserving surgery (BCS) and its value in prognosis are not clear. METHODS: A systematic research review was conducted using electronic database. The rate of clinical complete response (cCR) in BCS after NAC and these pathological CR (PCR) and non-pCR BCS patients' local recurrence-free survival (LRFS), distance recurrence-free survival (DRFS), overall survival (OS), and disease-free survival (DFS) rates were collected. A pooled analysis was performed using a fixed or random effects model and a Q test to determine heterogeneity. RESULTS: Sixteen studies with a total of 4639 patients were included. The pooled data revealed that cCR patients compared with non-cCR patients had significantly higher rates of BCS, with a summary estimate odds ratios (OR) of 4.54 (95% CI 2.03-10.17). The pooled data revealed that BCS patients who achieved pCR after NAC had significantly lower rates of LRFS (RR = 0.59, 95% CI 0.38-0.92) and DRFS (RR = 0.27, 95% CI 0.13-0.55). Better DFS (RR = 0.09, 95% CI 0.04-0.25) and OS (RR = 0.36, 95% CI 0.03-3.90) were also seen, but OS was not significantly different. CONCLUSIONS: The rate of successful BCS is higher in the cCR group than in the non-cCR group, means cCR after NAC can encourage patients to receive BCS. The achievement of pCR after NAC in BCS patients was associated with a good prognosis in terms of LRFS and DRFS, but its value in DFS and OS requires further investigation.

Diabetes and risk of anastomotic leakage after gastrointestinal surgery.

BACKGROUND: Anastomotic leakage (AL) is one of the most common and lethal complications in gastrointestinal surgery. However, the relationship between AL risk and diabetes mellitus (DM) remains ambiguous. This meta-analysis was to evaluate the association between DM and AL risk in patients after gastrointestinal resection. METHODS: Odds ratios (OR) estimate with their corresponding 95% confidence intervals (CIs) were combined and weighted to produce pooled OR using the fixed-effects model. Relative risks were calculated in subgroup analysis of prospective studies. We calculated publication bias by Begg rank correlation test and Egger linear regression test. RESULTS: DM was significantly and independently associated with an increased risk of AL morbidity in colorectal patients, 1.661 times in total patients (95% CIs = 1.266-2.178), 1.995 times in a subgroup of case-control studies, 1.581 times in cohort investigations, 1.688 times in retrospective trials, and 1.562 times in prospective designs. After adjusting for the factor of obesity and/or body mass index in the subgroup analyses of colorectal surgery, DM patients without obesity experienced a significantly increased risk of AL (OR = 1.572, 95% CIs = 1.112-2.222). Furthermore, when obesity had not been adjusted, DM patients endured a dramatical increase of AL incidence (OR = 1.812, 95% CIs = 1.171-2.804). Perforation incidence after gastric resection showed borderline association with DM (OR = 2.170, 95% CIs = 0.956-4.926). CONCLUSIONS: The present meta-analysis provides strong evidence for the first time that DM is significantly and independently associated with an increased risk of AL mortality in colorectal surgery.

Breast-conserving therapy: a viable option for young women with early breast cancer--evidence from a prospective study.

BACKGROUND: This study evaluated the security of breast-conserving treatment (BCT) in young patients and the effect of regional radiation therapy on young patients with 1-3 positive nodes (N+) treated with BCT. METHODS: In this prospective concurrent controlled study, 164 patients were defined as the BCT group, and regional radiation therapy was delivered to patients with 1-3 N+. Modified radical mastectomies (MRMs) were performed on 224 patients without regional radiation therapy. RESULTS: The 9-year local recurrence (LR) rate of the BCT was 7 %, compared with 3 % in the MRM group (p = 0.055). The 9-year regional recurrence (RR) rate was 6 % for the BCT group and 12 % for the MRM group (p = 0.048). The distant metastasis (DM)-free and breast cancer-specific survival rates were similar between the two groups. RR was an independent prognostic factor for DM [hazard ratio 3.27; 95 % confidence interval (CI) 1.726-6.208] and breast cancer-specific survival (hazard ratio 5.814; 95 % CI 2.690-12.568), whereas LR was not an independent prognostic factor for DM or breast cancer-specific survival. CONCLUSIONS: Young patients treated with BCT have a higher LR rate than that of MRM. However, LR has no detrimental effect on DM-free and breast cancer-specific survival rates, whereas RR is a strong risk factor of DM and death. Regional radiation therapy for young patients with 1-3 N+ may reduce RR and improve survival rates.

Effect of vascular haemoglobin concentrations on ultrasound-guided diffuse optical tomography in differentiating benign from malignant breast lesions.

OBJECTIVES: Ultrasound-guided diffuse optical tomography (US-DOT) can potentially detect breast carcinomas by measuring total tumour haemoglobin concentrations (TTHC). The purpose of this study was to evaluate whether vascular haemoglobin concentrations (VHC) affect the ability of US-DOT to distinguish breast carcinomas from benign. MATERIALS AND METHODS: In 85 women (97 palpable lesions) referred for core breast biopsy, we measured VHC with a complete blood count and calculated TTHCs for each lesion with US-DOT. Anaemia was defined as a VHC less than 120.0 g/L. RESULTS: Mean TTHCs were significantly higher in malignant lesions (n = 53) than in benign lesions (n = 44), regardless of whether the lesions were from women with anaemia (TTHC, 248.5 vs. 123.3 µmol/L; P = 0.001) or from those without (TTHC, 229.7 vs. 173.9 µmol/L; P = 0.016). A cut-off TTHC of 155.1 µmol/L provided 81.3 % sensitivity, 81.8 % specificity and 81.5 % accuracy for detecting malignant tumours in women with anaemia and 78.4 % sensitivity, 54.5 % specificity and 67.1 % accuracy for women without. There was no significant difference in sensitivity (P = 0.813), specificity (P = 0.108) and accuracy (P = 0.162) between the anaemic group and the non-anaemic group. CONCLUSIONS: Vascular haemoglobin concentrations did not affect the ability of US-DOT to differentiate breast carcinomas from benign lesions. KEY POINTS: • US-DOT can differentiate benign from malignant breast lesions by measuring TTHC. • No difference in TTHC between the anaemia and non-anaemia group. • Vascular haemoglobin concentrations do not affect the diagnostic ability of US-DOT.

RNA modification gene WDR4 facilitates tumor progression and immunotherapy resistance in breast cancer.

INTRODUCTION: Growing interest toward RNA modification in cancer has inspired the exploration of gene sets related to multiple RNA modifications. However, a comprehensive elucidation of the clinical value of various RNA modifications in breast cancer is still lacking. OBJECTIVES: This study aimed to provide a strategy based on RNA modification-related genes for predicting therapy response and survival outcomes in breast cancer patients. METHODS: Genes related to thirteen RNA modification patterns were integrated for establishing a nine-gene-containing signature-RMscore. Alterations of tumor immune microenvironment and therapy response featured by different RMscore levels were assessed by bulk transcriptome, single-cell transcriptome and genomics analyses. The biological function of key RMscore-related molecules was investigated by cellular experiments in vitro and in vivo, using flow cytometry, immunohistochemistry and immunofluorescence staining. RESULTS: This study has raised an effective therapy strategy for breast cancer patients after a well-rounded investigation of RNA modification-related genes. With a great performance of predicting patient prognosis, high levels of the RMscore proposed in this study represented suppressive immune microenvironment and therapy resistance, including adjuvant chemotherapy and PD-L1 blockade treatment. As the key contributor of the RMscore, inhibition of WDR4 impaired breast cancer progression significantly in vitro and in vivo, as well as participated in regulating cell cycle and mTORC1 signaling pathway via m7G modification. CONCLUSION: Briefly, this study has developed promising and effective tactics to achieve the prediction of survival probabilities and treatment response in breast cancer patients.

Do tumor grade and location affect survival in esophageal squamous cell carcinoma? Survival analysis of 302 cases of pT3N0M0 esophageal squamous cell carcinoma.

BACKGROUND: The 7th edition of the American Joint Committee on Cancer (AJCC) cancer staging manual incorporates tumor grade and location for staging pT2-3N0M0 esophageal squamous cell carcinoma. Patients with pT3N0M0, classified as stage IIa according to the 6th edition of the AJCC cancer staging manual, can now be classified as stage Ib, IIa, or IIb. We aimed to discuss whether these changes affect survival and determine other potential prognostic factors. METHODS: We retrospectively analyzed 302 patients with postoperative pathologic stage T3N0M0 who underwent esophagectomy between 1990 and 2005 at Sun Yat-sen University Cancer Center. We performed univariate and multivariate analyses to identify prognostic factors for survival and used the Kaplan-Meier method to compare survival difference in each prognostic factor, including tumor grade and location. RESULTS: The 5-year overall survival rate was 46 %, with a median survival of 1,244.5 days. Gender, age, alcohol consumption, forced expiratory volume in 1 s (FEV1), and number of removed lymph nodes were independent prognostic factors in both univariate and multivariate analyses. Smoking was also a prognostic factor in survival analysis by the Kaplan-Meier method. However, histologic tumor grade and location had no significant influence on patient survival. CONCLUSIONS: Age, gender, alcohol consumption, FEV1, number of removed lymph nodes, and cigarette smoking are independent prognostic factors in patients with pT3N0M0 esophageal squamous cell carcinoma. However, tumor grade and location may not be as strong predictors in these patients as indicated in the 7th edition of the AJCC cancer staging manual.

Synergistic effects of curcumin with emodin against the proliferation and invasion of breast cancer cells through upregulation of miR-34a.

Curcumin, a biphenyl compound derived from rhizome, is a powerful anti-cancer agent. Emodin is an active component isolated from the root and rhizome of Rheum palmatum that has been widely used in traditional Chinese medicine for the treatment of various diseases. Currently, there are no studies examining the effect of curcumin in combination with emodin on tumor cell growth. In this study, we report for the first time that combined curcumin and emodin administration synergistically inhibits proliferation (MTT assay), survival (flow cytometry), and invasion (transwell migration assay) of breast cancer cells. Synergism is determined by the Chou-Talalay method. Moreover, we demonstrate that miR-34a is upregulated by curcumin and emodin. This microRNA helps mediate the anti-tumor effects of curcumin and emodin by downregulating Bcl-2 and Bmi-1. Our results not only provide insight into the mechanism of synergy between curcumin and emodin in breast cancer cells, but also suggest a new and potentially useful approach for breast cancer therapy.

Targeted expression of miR-34a using the T-VISA system suppresses breast cancer cell growth and invasion.

Recurrence and metastasis result in a poor prognosis for breast cancer patients. Recent studies have demonstrated that microRNAs (miRNAs) play vital roles in the development and metastasis of breast cancer. In this study, we investigated the therapeutic potential of miR-34a in breast cancer. We found that miR-34a is downregulated in breast cancer cell lines and tissues, compared with normal cell lines and the adjacent nontumor tissues, respectively. To explore the therapeutic potential of miR-34a, we designed a targeted miR-34a expression plasmid (T-VISA-miR-34a) using the T-VISA system, and evaluated its antitumor effects, efficacy, mechanism of action, and systemic toxicity. T-VISA-miR-34a induced robust, persistent expression of miR-34a, and dramatically suppressed breast cancer cell growth, migration, and invasion in vitro by downregulating the protein expression levels of the miR-34a target genes E2F3, CD44, and SIRT1. In an orthotopic mouse model of breast cancer, intravenous injection of T-VISA-miR-34a:liposomal complex nanoparticles significantly inhibited tumor growth, prolonged survival, and did not induce systemic toxicity. In conclusion, T-VISA-miR-34a lead to robust, specific overexpression of miR-34a in breast cancer cells and induced potent antitumor effects in vitro and in vivo. T-VISA-miR-34a may provide a potentially useful, specific, and safe-targeted therapeutic approach for breast cancer.

Signet-ring cell carcinoma of the breast: a case report.

Signet-ring cell carcinoma (SRCC) can arise from virtually all organs. However, primary SRCC of the breast is very rare. Until 2003, SRCC was placed under 'mucin-producing carcinomas' and separated from other carcinomas by the World Health Organization (WHO). To date, only a few cases have been reported. A case of a 46-year-old woman with primary SRCC of the breast is presented in this report. The patient underwent a right modified radical mastectomy with axillary lymph node dissection. Characteristic features and differential diagnosis of this tumor are discussed in the light of pertinent literature.

[Expression of suppressor of cytokine signaling-3 and caspase-3 in endometriosis and their correlation].

OBJECTIVE: To investigate the expression of suppressor of cytokine signaling(SOCS)-3 and caspase-3 and their correlative significance in endometriosis. METHODS: Immunohistochemical EnVision method was used to detect the SOCS-3 and caspase-3 protein expression in ectopic and eutopic endometrium (n = 32) of patients with endometriosis, as well as normal endometrium (n = 30) of women without endometriosis. RESULTS: SOCS-3 and caspase-3 proteins were expressed in all three groups and not affected by the menstrual cycles. The expression of SOCS-3 in ectopic endometrium (5.54 ± 2.12) was significantly lower than that in eutopic (7.39 ± 1.09, P = 0.001) and control group (7.48 ± 1.26, P < 0.01), but without difference between the eutopic and control group (P = 0.756). SOCS-3 expression in ectopic and eutopic endometrium was significantly lower in III/IV stages than that in I/II stages of endometriosis (P < 0.05). Significantly lower expression of caspase-3 protein was found in ectopic (3.20 ± 1.24) and eutopic endometrium (3.88 ± 1.93) as compared with the control group (6.49 ± 1.85, P < 0.01), however ectopic and eutopic endometrium showed no significant difference (t = 1.66, P = 0.10). There was no significant difference of the expression of caspase-3 in ectopic and eutopic endometrium at different disease stages (P > 0.05). Positive correlation was found between the expression of SOCS-3 and caspase-3 proteins in ectopic endometrium (r = 0.655, P < 0.01). CONCLUSION: SOCS-3 may be involved in the development of endometriosis through inhibition of apoptosis of ectopic endometrial cells.

Predicting the immune microenvironment and prognosis with a anoikis - related signature in breast cancer.

Background: Tumor heterogeneity is widely recognized as a crucial factor impacting the prognosis of breast cancer (BC) patients. However, there remains an insufficient understanding of the underlying impact of anoikis on the prognosis of BC patients. Methods: The researchers utilized the TCGA-BRCA dataset to screen and analyze the differentially expressed genes of anoikis-related genes (ARGs) in BC and normal breast tissue. Prognostic gene signatures were established through univariate, LASSO, and multivariate Cox regression analyses. These signatures were evaluated using Kaplan-Meier curve and receiver operating characteristic (ROC) analyses, resulting in the development of an anoikis-related index (ACI). The training dataset was TCGA-BRCA, while METABRIC and GSE96058 were used for external validation. Additionally, nomograms were developed by combining risk scores and clinical parameters, enabling gene set enrichment analysis (GSEA) and tumor immunoassay. Furthermore, an exploration of small molecule compounds was conducted to identify potential therapeutic benefits. Results: A six-gene anoikis-related signature was constructed, which divided BC patients into high- and low-ACI groups based on median ACI scores. The ACI accurately predicted prognosis and acted as an independent prognostic factor for BC patients. Patients in the high-ACI group exhibited poorer overall survival (OS) across all cohorts and showed more severe clinical manifestations compared to the low-ACI group. The study also explored the potential impacts of anoikis on immune cells infiltrating tumors, immune checkpoints, growth factors, and cytokine levels. Additionally, the potential implications of anoikis in BC immunotherapy were discussed, along with highlighting small molecule compounds that could offer therapeutic benefits. Conclusions: Anoikis was found to hold significant prognostic value in breast cancer, providing a novel approach for managing patients with different prognoses and implementing more precise immunotherapy strategies.

Regulations of Exosomal-Transmitted AFAP1-AS1 LncRNA on Ovarian Cancer Cell Migration and Invasion.

BACKGROUND: Adolescent ovarian cancer (OC) has high malignancy. Long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of various malignancies, but their role in adolescent OC remains poorly understood. This study aims to assess the modulatory role of Exosome-transmitted lncRNA Actin filament-associated protein 1 Antisense RNA 1 (AFAP1-AS1) on the activity of OC cells. METHODS: We recruited a cohort of 40 adolescent patients diagnosed with OC and a control group of 40 healthy individuals. Serum samples were collected from both groups prior surgical intervention. Exosomes from peripheral blood and ascites were collected via differential centrifugation. The expression levels of AFAP1-AS1 in OC tissues and cell lines (IOSE-80, CAOV3, and SKOV3) were quantified using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The exosomal particle size and surface markers were characterized through nanoparticle tracking analysis and transmission electron microscopy. Furthermore, siRNA-mediated knockdown of AFAP1-AS1 was performed in IOSE-80, CAOV3, and SKOV3 cell lines. Functional assays, including wound-healing experiments and Transwell migration assays, were conducted to evaluate cellular migration and metastasis. RESULTS: Our findings demonstrate that the expression of AFAP1-AS1 is significantly upregulated in OC patients' serum exosomes and ascitic fluid, correlating with unfavorable pathological features such as advanced federation international of gynecology and obstetrics (FIGO) stage and larger tumor diameter. In-vitro experiments revealed that OC cell lines and primary human OC cells showed enhanced proliferation and metastasis when exposed to ascites-derived exosomes enriched in AFAP1-AS1. Importantly, we observed that AFAP1-AS1 can be transmitted to neighboring cells via exosomal pathways. Additionally, exosomes isolated from ascites treated with siRNA targeting AFAP1-AS1 can inhibit cellular migration and invasion. CONCLUSIONS: Our data provide evidence for the oncogenic role of AFAP1-AS1, which is transmitted via exosomes. This finding has significant implications for understanding the molecular mechanisms of AFAP1-AS1 in the pathogenesis of adolescent ovarian cancer.

Novel Implication of the Basement Membrane for Breast Cancer Outcome and Immune Infiltration.

Therapeutic failure in breast cancer patients is largely attributed to postoperative advancement and therapy resistance. Nevertheless, an efficacious prognostic signature for recognizing this population is lacking. The basement membrane (BM) has been proven to be strongly involved in cancer progression and metastasis, and has the potential to be a powerful predictor in breast cancer. In this study, substantial bulk RNA transcriptomics, single cell RNA transcriptomics and clinical information were collected from TCGA-BRCA, METABRIC and GSE96058, and Kaplan-Meier survival curves, single cell analysis and in vitro experiments were conducted to validate the signature. From the results, a prognostic index, namely, the BMscore, was established with six pivotal BM genes, specifically LOXL1, FBLN1, FBLN5, SDC1, ADAMTS8 and PXDNL. Verification by independent cohorts showed that breast cancer patients with high BMscore had a distinctly worse outcome. By integrating the BMscore and clinical factors, we constructed a prognostic nomogram that displayed good predictive capability. Furthermore, we evaluated the implication of the BMscore in breast cancer immune infiltration. More importantly, a strongly positive correlation between the BMscore and EMT activity was revealed with immunohistochemistry and in vitro experiments. Taken together, we provided a novel BMscore gene signature for breast cancer patients to predict clinical prognosis and metastasis accurately, which may help with individualized clinical decision-making.

A case report of primary small cell carcinoma of the breast and review of the literature.

Primary small cell carcinoma (SCC) of the breast, an exceedingly rare and aggressive tumor, is often characterized by rapid progression and poor prognosis. We report a case of primary SCC of the breast that was diagnosed through pathologic and immunohistochemical examinations. Computed tomography (CT) scans failed to reveal a non-mammary primary site. Due to the scant number of relevant case summaries, this type of tumor is proved to be a diagnostic and therapeutic challenge. Therefore, we also reviewed relevant literature to share expertise in diagnosis, clinicopathologic characteristics, treatment, and prognosis of this type of tumor. Future studies with more cases are required to define more appropriate treatment indications for this disease.

The Influence of Hormone Therapy on secondary diabetes mellitus in Breast Cancer: A Meta-analysis.

BACKGROUND: Growing evidences have implied that patients with primary breast cancer (BC) were at increased risks of developing diabetes mellitus (DM). However, as a major adjuvant treatment, the influence of hormone therapy (HT) on secondary DM in primary BC remains controversial; we conducted a meta-analysis of existing studies to evaluate the association of hormone therapy and secondary DM. METHODS: We searched online databases (PubMed, EMBASE, the Cochrane library, Scopus, and Google Scholar) for studies exploring the influence of hormone therapy on secondary DM in BC. The summarized effect sizes (ES) and 95% confidence interval (95% CI) are calculated by STATA software utilizing fixed-effect or random-effect models, depending on the heterogeneity of the eligible studies. RESULTS: Ultimately, 7 retrospective publications including a total of 44,524 primary BC patients are eligible in present meta-analysis. HT use significantly increased the risk of developing DM in primary BC patients, whenever compared with NON-HT BC patients (pooled adjusted HR 1.30, 95% CI: 1.19-1.43) or NORMAL participants (HR 1.19, 95% CI: 1.14-1.25). As to specific HT medications, our sub-analysis demonstrates the risk for DM in tamoxifen (TAM) users elevates by 30% than NON-TAM use BC patients (pooled HR 1.30, 95% CI: 1.20-1.40) and by 18% than NORMAL participants (pooled HR 1.18, 95% CI: 1.12-1.24). However, for aromatase inhibitors (AIs) users, the risks for DM do not elevate significantly. Funnel plots and Egger's tests are used to evaluate publication bias and no apparent bias is detected in all analysis. CONCLUSION: The present study is the first meta-analysis which thoroughly reveals that adjuvant HT is a risk factor of secondary DM in primary female BC patients. As to specific HT medications, TAM use significantly enhances the incidence of secondary DM, while AIs use does not influence the DM incidence significantly. Our results can help clinicians to tailor more appropriate strategies for the therapy and follow-up of primary BC patients.

DAB2IP attenuates chemoresistance of triple-negative breast cancer through sequestration of RAC1 to prevent ß-catenin nuclear accumulation.

BACKGROUND: Although chemotherapy, the most widely used systemic treatment in triple-negative breast cancer (TNBC), markedly improved the patients' outcome, chemoresistance always occurs. This study purposed to explore new therapeutic strategies for the treatment of chemoresistance. METHODS AND RESULTS: The expression and prognostic value of DAB2IP were investigated in TNBC tissues and cell lines. Low DAB2IP expression predicted high mortality risk in TNBC. Inhibition of DAB2IP expression conferred cancer stem cell capacity and chemoresistance in TNBC cell lines. Using murine breast cancer (BC) xenograft models, we evaluated the association with DAB2IP and chemoresistance. DAB2IP inhibited TNBC tumourigenesis and chemoresistance in vivo. Further, we revealed that DAB2IP inhibited ß-catenin nuclear transport through competitive interaction with RAC1 and decreased ß-catenin accumulation in the cell nucleus. Finally, we found that the DNA methylation level was negatively associated with DAB2IP expression in TNBC. Inhibition of DNA methylation restored the DAB2IP expression and attenuated chemoresistance in TNBC. CONCLUSIONS: We revealed that DAB2IP attenuates chemoresistance of TNBC via inhibition of RAC1-mediated ß-catenin nuclear accumulation. Decitabine treatment results in re-expression of DAB2IP by inhibiting DNA methylation and could be a potential therapeutic strategy for chemoresistance in TNBC.

Comparison of the Characteristics and Prognosis Between Very Young Women and Older Women With Breast Cancer: A Multi-Institutional Report From China.

Purpose: Our understanding of breast cancer in very young women (≤35 years old) remains limited. We aimed to assess the clinicopathological characteristics, molecular subtype, and treatment distribution and prognosis of these young patients compared with patients over 35 years. Methods: We retrospectively analyzed non-metastatic female breast cancer cases treated at three Chinese academic hospitals between January 1, 2008, and December 31, 2018. Local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were compared between different age groups and stratified with distinct molecular subtypes. Results: A total of 11,671 women were eligible for the final analyses, and 1,207 women (10.3%) were ≤35 years at disease onset. Very young breast cancer women were more likely to be single or childless, have higher-grade disease, have more probability of lymphovascular invasion (LVI) in tumor and triple-negative subtype, and be treated by lumpectomy, chemotherapy especially more anthracycline- and paclitaxel-based chemotherapy, endocrine therapy plus ovarian function suppression (OFS), anti-HER2 therapy, and/or radiotherapy than older women (P < 0.05 for all). Very young women had the lowest 5-year LRFS and DFS among all age groups (P < 0.001 for all). When stratified by molecular subtype, very young women had the worst outcomes vs. women from the 35~50-year-old group or those from >50-year-old group for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) subtype, including LRFS, DFS, and OS (P < 0.05 for all). In terms of LRFS and DFS, multivariate analyses showed similar results among the different age groups. Conclusion: Our study demonstrated that very young women with breast cancer had higher-grade tumors, more probability of LVI in tumor, and more triple-negative subtype, when compared with older patients. They had less favorable survival outcomes, especially for patients with the HR+/HER2- subtype.

Prognosis stratification in breast cancer and characterization of immunosuppressive microenvironment through a pyrimidine metabolism-related signature.

Pyrimidine metabolism is a hallmark of cancer and will soon become an essential part of cancer therapy. In the tumor microenvironment, cells reprogram pyrimidine metabolism intrinsically and extracellularly, thereby promoting tumorigenesis. Metabolites in pyrimidine metabolism have a significant impact on promoting cancer advancement and modulating immune system responses. In preclinical studies and practical clinical applications, critical targets in pyrimidine metabolism are acted upon by drugs to exert promising therapeutic effects on tumors. However, the pyrimidine metabolism in breast cancer (BC) is still largely underexplored. In this study, 163 credible pyrimidine metabolism-related genes (PMGs) were retrieved, and their somatic mutations and expression levels were determined. In addition, by using The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases, 12 PMGs related to the overall survival (OS) were determined using the univariate Cox regression analysis. Subsequently, by performing the LASSO Cox hazards regression analysis in the 12 PMGs in TCGA-BRCA dataset, we developed a prognosis nomogram using eight OS-related PMGs and then verified the same in the METABRIC, GSE96058, GSE20685, GSE42568 and GSE86166 data. Moreover, we validated relationships between the pyrimidine metabolism index (PMI) and the survival probability of patients, essential clinical parameters, including the TNM stage and the PAM50 subtypes. Next, we verified the predictive capability of the optimum model, including the signature, the PAM50 subtype, and age, using ROC analysis and calibration curve, and compared it with other single clinical factors for the predictive power of benefit using decision curve analysis. Finally, we investigated the potential effects of pyrimidine metabolism on immune checkpoints, tumor-infiltrating immune cells, and cytokine levels and determined the potential implications of pyrimidine metabolism in BC immunotherapy. In conclusion, our findings suggest that pyrimidine metabolism has underlying prognostic significance in BC and can facilitate a new management approach for patients with different prognoses and more precise immunotherapy.