Predictive and prognostic effect of HO-1 expression in breast cancer patients undergoing neoadjuvant chemotherapy.

PURPOSE: Heme oxygenase-1 (HO-1) has complex biological function, and is a candidate oncogene with a wide variety of deleterious functions in breast cancer. Here, we evaluated the relationship between expression of HO-1 protein with clinical response to neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS: We used immunohistochemistry (IHC) to determine expression of HO-1 protein from core needle biopsy before NAC, then applied univariate and multivariate analyses to understand the relationship between HO-1 with pathological complete response (pCR) outcomes. Next, Kaplan-Meier and Log-rank tests were used to compare disease-free survival (DFS) and overall survival (OS), between groups, and Cox proportional hazards regression analysis applied for prognostic evaluation. RESULTS: A total of 575 patients with locally advanced invasive breast cancer were included in the study, of which 111 (19.3%) achieved pCR after NAC. Results from multivariate analysis showed that high HO-1 expression was an independent predictor of low pCR rate (OR 0.254, 95% CI 0.026-0.643, p = 0.002). Moreover, results from survival analysis showed that high HO-1 expression was significantly associated with shorter DFS (HR 4.843, 95% CI 1.205-32.572, p = 0.026), but not with OS (HR 3.219, 95% CI 0.928-32.124, p = 0.071). Furthermore, HO-1 expression was significantly associated with lower pCR rate (OR 0.102, 95% CI 0.013-0.352), p = 0.001), poor DFS (HR 8.562, 95% CI 1.592-34.950, p = 0.009), and OS (HR 7.835, 95% CI 1.220-56.213, p = 0.023) of patients with triple-negative breast cancer (TNBC) patients. CONCLUSION: Our results indicated that HO-1 expression is not only a biomarker for predicting pCR, but also a prognostic factor in breast cancer patients in a neoadjuvant setting, especially in TNBC subgroups.

Triptolide Suppresses Growth of Breast Cancer by Targeting HMGB1 in Vitro and in Vivo.

Triptolide has been indicated potent anti-cancer effect involving multiple molecular targets and signaling pathways. High-mobility group box 1 (HMGB1) is a highly conserved DNA-binding protein taking part in breast cancer development. The therapeutic effect of triptolide on HMGB1 has not been reported. Thus, our study aims to clarify the role of HMGB1 in triptolide-induced anti-growth effect on breast cancer in vitro and in vivo. We demonstrated that triptolide significantly suppressed growth of breast cancer cells by inhibition of cell viability, clonogenic ability. Further studies evidenced that triptolide treatment not only inhibited HMGB1 mRNA expression, but also decreased supernatant level of HMGB1 in vitro. In line with these observations, exogenous recombinant HMGB1 (rHMGB1) promoted cell proliferation of breast cancer, and triptolide reversed the rHMGB1-promoted proliferative effect. As well, triptolide enhanced the anti-proliferative activity of ethyl pyruvate (EP) (HMGB1 inhibitor). Furthermore, downstream correlation factors (Toll-like receptor 4 (TLR4) and phosphorylated-nuclear factor-kappaB (NF-κB) p65) of HMGB1 were significantly decreased in vitro after triptolide treatment. Consistantly, we confirmed that tumor growth was significantly inhibited after triptolide treatment in vivo. Meanwhile, immunohistochemical analyses showed that triptolide treatment significantly decreased the level of cytoplasmic HMGB1 and TLR4 expression, whereas the expression of NF-κB p65 was relatively higher in cytoplasm, and conversely lower in nucleus as compared to the control group. Collectively, these results demonstrate that triptolide suppresses the growth of breast cancer cells via reduction of HMGB1 expression in vitro and in vivo, which may provide new insights into the treament of breast cancer.

A Novel Animal Model of Induced Breast Precancerous Lesion in Tree Shrew.

Chinese tree shrew, an animal exhibited closer evolutionary relationship with humans compared to rodents, is getting increasingly attentions as an appealing experimental animal model for human diseases. However, a high-efficiency and stable method to establish tree shrew breast precancerous lesions model has not been clearly elucidated. Thus, the current study aimed to explore the way of establishing breast precancerous model in tree shrew and investigate the pathologic characteristics of induced breast precancerous lesions. The results indicated that 7,12-dimethylbenz(a)anthracene (DMBA) could induce breast lesions in tree shrews. However, comparing to DMBA alone, an addition of medroxyprogesterone acetate (MPA) to DMBA critically increased the rate of induced breast lesion in tree shrews. Half of induced breast lesions were intraductal papilloma and the others were atypical ductal hyperplasia. Induced lesions showed positive expression of estrogen receptor α (ERα), progesterone receptor (PR) and cytokeratin 5/6 (CK5/6), but negative expression of human epidermal growth factor receptor-2 (Her-2). The expression of B cell lymphoma-extra large (Bcl-xl) was significantly higher and the expression of B cell lymphoma 2 associated X protein (Bax) was significantly lower in the precancerous lesions (atypical ductal hyperplasia) compared to benign tumor (intraductal papilloma). These results suggest that DMBA is able to induce breast lesions in tree shrews. Combination of DMBA and MPA may be more effective to establish breast precancerous lesion tree shrew models. Tree shrew might be a promising animal model for studying the tumorogenesis of breast cancer.

[Effects of FBI-1 silencing on proliferation and apoptosis of triple-negative breast cancer cell line MDA-MB-231].

This work aimed to observe the effects of short hairpin RNA (shRNA)-silenced FBI-1 (factor that binds to the inducer of short transcripts of human immunodeficiency virus-1) on proliferation and apoptosis of triple-negative breast cancer cell line MDA-MB-231. qRT-PCR and Western blot analysis were applied to detect the mRNA and/or protein expression of FBI-1, Bcl-2, Bax, cleaved-Caspase 3 and Survivin. RNA interference method was used to silence FBI-1 expression in MDA-MB-231 cells. CCK-8 and colony formation assay were employed to detect the cell proliferation. Flow cytometry was employed for examining cell apoptosis. In vivo tumorigenicity of MDA-MB-231 cells was detected by tumor transplantation in nude mice. The results showed that the mRNA and protein expressions of FBI-1 were higher in MDA-MB-231 cells compared with those in normal human mammary epithelial cells MCF-10A. FBI-1 gene silencing inhibited proliferation and induced apoptosis of MDA-MB-231 cells in vitro, together with decreased Bcl-2 and Survivin protein expression, increased Bax protein expression and activated Caspase 3. Moreover, FBI-1 gene silencing inhibited the tumorigenesis of MDA-MB-231 cells in vivo. These results suggest that silencing of FBI-1 gene inhibits proliferation, induces apoptosis and suppresses the tumorigenesis of MDA-MB-231 cells.

Src/STAT3-dependent heme oxygenase-1 induction mediates chemoresistance of breast cancer cells to doxorubicin by promoting autophagy.

Chemotherapeutic resistance in breast cancer, whether acquired or intrinsic, remains a major clinical obstacle. Thus, increasing tumor cell sensitivity to chemotherapeutic agents will be helpful in improving the clinical management of breast cancer. In the present study, we found an induction of HO-1 expression in doxorubicin (DOX)-treated MDA-MB-231 human breast adenocarcinoma cells, which showed insensitivity to DOX treatment. Knockdown HO-1 expression dramatically upregulated the incidence of MDA-MB-231 cell death under DOX treatment, indicating that HO-1 functions as a critical contributor to drug resistance in MDA-MB-231 cells. We further observed that DOX exposure induced a cytoprotective autophagic flux in MDA-MB-231 cells, which was dependent on HO-1 induction. Moreover, upregulation of HO-1 expression required the activation of both signal transducer and activator of transcription (STAT)3 and its upstream regulator, protein kinase Src. Abrogating Src/STAT3 pathway activation attenuated HO-1 and autophagy induction, thus increasing the chemosensitivity of MDA-MB-231 cells. Therefore, we conclude that Src/STAT3-dependent HO-1 induction protects MDA-MB-231 breast cancer cells from DOX-induced death through promoting autophagy. In the following study, we further demonstrated the contribution of Src/STAT3/HO-1/autophagy pathway activation to DOX resistance in another breast cancer cell line, MDA-MB-468, which bears a similar phenotype to MDA-MB-231 cells. Therefore, activation of Src/STAT3/HO-1/autophagy signaling pathway might play a general role in protecting certain subtypes of breast cancer cells from DOX-induced cytotoxicity. Targeting this signaling event may provide a potential approach for overcoming DOX resistance in breast cancer therapeutics.

Locoregional recurrence and survival of breast-conserving surgery compared to mastectomy following neoadjuvant chemotherapy in operable breast cancer.

Background: The risk of locoregional recurrence (LRR) and the long-term prognosis of breast-conserving surgery (BCS) after neoadjuvant chemotherapy (NAC) are still controversial. This study aimed to evaluate oncological outcomes for patients undergoing BCS after NAC and determine LRR and survival predictors. Methods: This study was a retrospective cohort study of patients with locally advanced breast cancer (LABC) who received NAC and underwent BCS or mastectomy from June 2011 to November 2020. LRR, disease-free survival (DFS), and overall survival (OS) were compared in patients undergoing BCS or mastectomy. Univariate and multivariate analyses were performed to determine LRR, DFS, and OS predictors. Results: A total of 585 patients were included, of whom 106 (18.1%) underwent BCS and 479 (81.9%) underwent a mastectomy. The LRR rate was 11.3% in the BCS group and 16.3% in the mastectomy group, revealing no significant difference(p = 0.200). In patients who underwent BCS, clinical lymph node status, histological grade and pathological complete response (pCR) were independent factors to predict LRR. There was no significant difference in DFS and OS between the BCS and the mastectomy groups. Multivariable analysis showed that lymph node status, histological grade, molecular subtypes, pCR and Miller&Payne (M&P) classification were independent predictors of DFS. Lymph node status, molecular subtypes and pCR were independent predictors of OS. BCS or mastectomy was not an independent predictor of DFS or OS. Conclusion: Compared with mastectomy, BCS after NAC may not increase the risk of local recurrence or mortality, BCS can be performed in selected patients with small tumor size and good response to NAC.

AI models predicting breast cancer distant metastasis using LightGBM with clinical blood markers and ultrasound maximum diameter.

Breast cancer metastasis significantly impacts women's health globally. This study aimed to construct predictive models using clinical blood markers and ultrasound data to predict distant metastasis in breast cancer patients, ensuring clinical applicability, cost-effectiveness, relative non-invasiveness, and accessibility of these models. Analysis was conducted on data from 416 patients across two centers, focusing on clinical blood markers (tumor markers, liver and kidney function indicators, blood lipid markers, cardiovascular biomarkers) and maximum lesion diameter from ultrasound. Feature reduction was performed using Spearman correlation and LASSO regression. Two models were built using LightGBM: a clinical model (using clinical blood markers) and a combined model (incorporating clinical blood markers and ultrasound features), validated in training, internal test, and external validation (test1) cohorts. Feature importance analysis was conducted for both models, followed by univariate and multivariate regression analyses of these features. The AUC values of the clinical model in the training, internal test, and external validation (test1) cohorts were 0.950, 0.795, and 0.883, respectively. The combined model showed AUC values of 0.955, 0.835, and 0.918 in the training, internal test, and external validation (test1) cohorts, respectively. Clinical utility curve analysis indicated the combined model's superior net benefit in identifying breast cancer with distant metastasis across all cohorts. This suggests the combined model's superior discriminatory ability and strong generalization performance. Creatine kinase isoenzyme (CK-MB), CEA, CA153, albumin, creatine kinase, and maximum lesion diameter from ultrasound played significant roles in model prediction. CA153, CK-MB, lipoprotein (a), and maximum lesion diameter from ultrasound positively correlated with breast cancer distant metastasis, while indirect bilirubin and magnesium ions showed negative correlations. This study successfully utilized clinical blood markers and ultrasound data to develop AI models for predicting distant metastasis in breast cancer. The combined model, incorporating clinical blood markers and ultrasound features, exhibited higher accuracy, suggesting its potential clinical utility in predicting and identifying breast cancer distant metastasis. These findings highlight the potential prospects of developing cost-effective and accessible predictive tools in clinical oncology.

Development and validation of AI models using LR and LightGBM for predicting distant metastasis in breast cancer: a dual-center study.

Objective: This study aims to develop an artificial intelligence model utilizing clinical blood markers, ultrasound data, and breast biopsy pathological information to predict the distant metastasis in breast cancer patients. Methods: Data from two medical centers were utilized, Clinical blood markers, ultrasound data, and breast biopsy pathological information were separately extracted and selected. Feature dimensionality reduction was performed using Spearman correlation and LASSO regression. Predictive models were constructed using LR and LightGBM machine learning algorithms and validated on internal and external validation sets. Feature correlation analysis was conducted for both models. Results: The LR model achieved AUC values of 0.892, 0.816, and 0.817 for the training, internal validation, and external validation cohorts, respectively. The LightGBM model achieved AUC values of 0.971, 0.861, and 0.890 for the same cohorts, respectively. Clinical decision curve analysis showed a superior net benefit of the LightGBM model over the LR model in predicting distant metastasis in breast cancer. Key features identified included creatine kinase isoenzyme (CK-MB) and alpha-hydroxybutyrate dehydrogenase. Conclusion: This study developed an artificial intelligence model using clinical blood markers, ultrasound data, and pathological information to identify distant metastasis in breast cancer patients. The LightGBM model demonstrated superior predictive accuracy and clinical applicability, suggesting it as a promising tool for early diagnosis of distant metastasis in breast cancer.

IKKα inhibition re-sensitizes acquired adriamycin-resistant triple negative breast cancer cells to chemotherapy-induced apoptosis.

IKKα has been shown to be responsible of multiple pro-tumorigenic functions and therapy resistance independent of canonical NF-κB, but its role in acquired chemotherapy resistance in breast cancer remains unclarified. In this study, we obtained pre-treatment biopsy and post-treatment mastectomy specimens from a retrospective cohort of triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy(NAC) (n = 43). Immunohistochemical methods were used to detect the expression of IKKα before and after NAC, and the relationship between IKKα and the pathologic response to NAC was examined. In addition, we developed a new ADR-resistant MDA-MB-231 cell line(MDA-MB-231/ADR) and analyzed these cells for changes in IKKα expression, the role and mechanisms of the increased IKKα in promoting drug resistance were determined in vitro and in vivo. We demonstrated that the expression of IKKα in residual TNBC tissues after chemotherapy was significantly higher than that before chemotherapy, and was positively correlated with lower pathological reaction. IKKα expression was significantly higher in ADR-resistant TNBC cells than in ADR-sensitive cells, IKKα knockdown results in apoptotic cell death of chemoresistant cells upon drug treatment. Moreover, IKKα knockdown promotes chemotherapeutic drug-induced tumor cell death in an transplanted tumor mouse model. Functionally, we demonstrated that IKKα knockdown significantly upregulated the expression of cleaved caspase 3 and Bax and inhibited the expression of Bcl-2 upon ADR treatment. Our findings highlighted that IKKα exerts an important and previously unknown role in promoting chemoresistance in TNBC, combining IKKα inhibition with chemotherapy may be an effective strategy to improve treatment outcome in chemoresistant TNBC patients.

Impact of Primary Site Surgery on Survival of Patients with de novo Stage IV Breast Cancer.

PURPOSE: The efficacy of primary site surgery in patients with de novo stage IV breast cancer remains controversial. However, few real-world studies have evaluated the benefits of local surgery on the primary site of stage IV breast cancer in China. The purpose of this study was to investigate the role of local surgery in the de novo stage IV breast cancer. MATERIALS AND METHODS: Women with metastatic breast cancer at diagnosis were identified from Guangxi medical university cancer hospital (China) database from 2009 to 2017. The clinical and tumor features, surgical treatment, and survival rates were compared between surgical and non-surgical patients. RESULTS: Two hundred forty-three patients were included, of whom 125 underwent primary site surgery. Patients who underwent surgery were more often had small primary tumors, fewer lymph node metastases, and had less visceral involvement. Patients in the surgery group had dramatically longer OS (median 35 vs 22 months, log-rank P=0.006). Stratified survival analysis showed that patients with bone metastasis alone or ≤3 metastasis benefit from surgery, while patients with visceral metastasis did not benefit from surgery. In multivariate analysis, surgical treatment, estrogen receptor status, progesterone receptor status and visceral metastases remained independent factors for survival. CONCLUSION: Surgical resection of the primary site can improve survival in selected de novo stage IV breast cancer patients.

Significance of Oncotype DX 21-Gene Test and Expression of Long Non-Coding RNA MALAT1 in Early and Estrogen Receptor-Positive Breast Cancer Patients.

OBJECTIVE: To investigate the association between the recurrence score (RS) obtained by Oncotype DX 21-gene test and long non-coding RNA (lncRNA) MALAT1 expression in early and estrogen receptor-positive (ER+) breast cancer. MATERIALS AND METHODS: The Oncotype DX 21-gene test and MALAT1 expression detection were performed in tumor samples from 76 ER+ and early breast cancer patients with the Surplex liquid chip. The RS value was calculated based on the expression of total 21 genes. The level of MALAT1 was measured in both tumor tissue and para-tumor tissue, and relatively quantified with an internal control gene. Mann-Whitney U-test or Kruskal-Wallis test were used to analyze the association between MALAT1 level and different clinical pathological characteristics, including age, tumor stage, disease grade, lymph node status, Ki-67 expression, and progesterone receptor (PR) status. The association between the RS and different characteristics was analyzed by Wilcoxon rank-sum test. Correlation between two parameters was analyzed by Spearman's rank correlation analysis. RESULTS: The expression of MALAT1 was more abundant in tumor tissue (2.992 ± 2.256) than that in adjacent normal tissue (1.641±1.438, Z=-2.594, p=0.009), and it was not correlated with any clinical pathological characteristics. According to the old criteria for RS stratification, 52.7% of patients were in low risk (RS<18), 36.8% of patients were in medium risk (18≤RS≤30), and 10.5% of patients were in high risk (RS>30). While under the new criteria, 18.4% were in low risk group (RS<11), 63.2% were in a medium risk group (11≤RS≤26), and 18.4% were in a high risk group (RS>26). The Oncotype DX 21-gene results only correlated with Ki-67 expression under both new and old criteria, and it was not related with other cancer characteristics. The expression of lncRNA MALAT1 was significantly correlated with the Oncotype DX 21-gene results under the old criteria. CONCLUSION: MALAT1 is a novel breast cancer biomarker independent of tumor stage, disease grade and lymph node status. MALAT1 level is associated with the Oncotype DX 21-gene RS value. Therefore, combination of MALAT1 and the Oncotype DX 21-gene test may be used to predict prognosis in ER+ and early stage breast cancer.

Capsaicin Inhibits Proliferation and Induces Apoptosis in Breast Cancer by Down-Regulating FBI-1-Mediated NF-κB Pathway.

BACKGROUND: As a natural compound extracted from a variety of hot peppers, capsaicin has drawn increasing attention to its anti-cancer effects against multiple human cancers including breast cancer. FBI-1 is a major proto-oncogene negatively regulating the transcription of many tumor suppressor genes, and plays a vital role in tumorigenesis and progression. However, whether FBI-1 is involved in capsaicin-induced breast cancer suppression has yet to be ascertained. This study aimed to investigate the effects of capsaicin on proliferation and apoptosis and its association with FBI-1 expression in breast cancer. METHODS: CCK-8 and morphological observation assay were employed to detect cell proliferation. Flow cytometry and TUNEL assay were conducted to detect cell apoptosis. RNA interference technique was used to overexpress or silence FBI-1 expression. qRT-PCR and/or Western blot analysis were applied to detect the protein expression of FBI-1, Ki-67, Bcl-2, Bax, cleaved-Caspase 3, Survivin and NF-κB p65. Xenograft model in nude mice was established to assess the in vivo effects. RESULTS: Capsaicin significantly inhibited proliferation and induced apoptosis in breast cancer in vitro and in vivo, along with decreased FBI-1, Ki-67, Bcl-2 and Survivin protein expression, increased Bax protein expression and activated Caspase 3. Furthermore, FBI-1 overexpression obviously attenuated the capsaicin-induced anti-proliferation and pro-apoptosis effect, accompanied with the above-mentioned proteins reversed, whereas FBI-1 silencing generated exactly the opposite response. In addition, as a target gene of FBI-1, NF-κB was inactivated by p65 nuclear translocation suppressed with capsaicin treatment, which was perceptibly weakened with FBI-1 overexpression or enhanced with FBI-1 silencing. CONCLUSION: This study reveals that FBI-1 is closely involved in capsaicin-induced anti-proliferation and pro-apoptosis of breast cancer. The underlying mechanism may be related to down-regulation of FBI-1-mediated NF-κB pathway. Targeting FBI-1 with capsaicin may be a promising therapeutic strategy in patients with breast cancer.

Prevalence of postmastectomy pain syndrome and associated risk factors: A large single-institution cohort study.

Postmastectomy pain syndrome (PMPS) is a frequent complication of breast surgery, and is considered a chronic neuropathic pain in the side of surgery which persists more than 3 months. We conducted a retrospective analysis of the largest reported cohort to investigate the prevalence of PMPS and to analyze its associated risk factors as well as the influence on quality of life (QoL). Two thousand thirty-three surgically-treated female patients diagnosed between 2012 and 2017 with early-stage breast cancer were asked to complete a questionnaire survey about their current chronic neuropathic pain problems and quality of life. Multivariate logistic regression analyses were applied to determine the associated risk factors of PMPS. Results have shown that 1983 (97.5%) patients responded and completed a questionnaire survey. Among them, PMPS was found in 28.2% of patients. In univariate analysis, age≤35 years, tumor staging, history of chronic pain, total mastectomy, and axillary lymph node dissection (ALND) were significantly correlated with PMPS (P < .05). Multivariate analysis showed that age≤35 years, history of chronic pain, total mastectomy, and ALND were the independent risk factors of PMPS. QoL outcomes have shown that the global QoL score, physical function score, role function score, and social function score in the PMPS group were reduced in the PMPS group (P < .05), while the difference in emotional function score and cognitive function score showed no statistical significance (P > .05). Besides, patients with PMPS have worse body image, sexual enjoyment, and more breast symptoms. In conclusion, PMPS is linked with a high incidence among breast cancer patients, and has a considerable negative influence on the quality of life. In addition, age, total mastectomy, ALND, and history of chronic pain are the independent risk factors of PMPS.

Sodium Butyrate Combined with Docetaxel for the Treatment of Lung Adenocarcinoma A549 Cells by Targeting Gli1.

PURPOSE: This study is aimed to investigate the combined treating efficacy of sodium butyrate and docetaxel on proliferation and apoptosis of the lung adenocarcinoma A549 cell line based on Gli1 regulation in vitro and in vivo. MATERIALS AND METHODS: RNA interference method was used to overexpress Gli1 in A549 cells. Cells were treated with varying concentrations of sodium butyrate, docetaxel or both in combination. CCK-8, colony formation assay, Hoechst 33258 staining, flow cytometry and TUNEL assay were employed to detect proliferation, cell cycle and apoptosis. qRT-PCR and Western blot analysis were applied to detect the mRNA and protein expression of Gli1. In vivo tumorigenicity was detected by tumor transplantation in nude mice. Downstream protein levels of Gli1 were detected using Western blot assay. RESULTS: It was found that sodium butyrate or docetaxel alone, respectively, inhibited proliferation and promoted apoptosis of A549 cells in vitro and in vivo, while the combination of the two generated significantly higher responses, which were also effective in another lung adenocarcinoma cell line H1299. Furthermore, the combined therapy had an additive effect in suppressing Gli1 expression and regulating the expression of its downstream proteins that involve in proliferation, cell cycle and apoptosis of A549 cells in vitro and in vivo, including decreased protein expression of Ki-67, CDK1, CDK2, Cyclin D1, Bcl-2 and Survivin, and increased protein expression of Cyclin A, p21, Bax and cleaved-Caspase 3. On the other hand, Gli1 overexpression perceptibly reversed the above-mentioned additive effect in vitro and in vivo. CONCLUSION: This study demonstrates that the combined therapy of sodium butyrate and docetaxel additively inhibits proliferation and promotes apoptosis of A549 lung adenocarcinoma cells via suppressing Gli1 expression in vitro and in vivo. Targeting Gli1 by the combined therapy may provide new insights into the therapeutic management of patients with lung adenocarcinoma.

Selective degradation of IKKα by autophagy is essential for arsenite-induced cancer cell apoptosis.

Two catalytic subunits of the IKK complex, IKKα and IKKß, trigger NF-κB activation as well as NF-κB-independent signaling events under both physiological and pathological conditions. Here we identified the NF-κB-unrelated cytoprotective function of IKKα in promoting autophagy by triggering p53 transactivation and upregulation of its downstream autophagic mediator, DRAM1, in the arsenite-treated hepatoma cells, which responses depended on IKKα kinase activity. Furthermore, IKKα triggered p53/DRAM1-dependent autophagy by inducing CHK1 activation and CHK1/p53 interaction. Interestingly, after provoking autophagy, IKKα could be specifically recognized by the autophagic machinery via directly binding with LC3B, resulting in selective degradation of IKKα by autophagy. Unexpectedly, the selectivity of autophagic sequestration towards IKKα was mediated by novel mechanism independent of the classical LC3-interacting regions (LIRs) within IKKα, while C-terminal arm of LIR was involved in mediating IKKα/LC3B interaction. Taken together, we conclude that IKKα attenuates arsenite-induced apoptosis by inducing p53-dependent autophagy, and then selective feedback degradation of IKKα by autophagy contributes to the cytotoxic response induced by arsenite.

Postoperative outcomes of breast reconstruction after mastectomy: A retrospective study.

Breast reconstruction after mastectomy plays an active role in improving the quality-of-life (QoL) and alleviating the psychological trauma of breast cancer patients, and has become an indispensable part of the comprehensive treatment in breast cancer. However, compared with mastectomy alone, breast reconstruction also increase operative complications. The surgical, oncological outcomes, and cosmetic effect of breast reconstruction remains to be evaluated. Data for patients with breast cancer who underwent breast reconstruction after mastectomy from February 2009 to November 2015 in our hospital were retrospectively analyzed, with a median follow-up time of 44 months. The operating time, blood loss, drainage fluid, postoperative complications, postoperative cosmesis, oncological outcomes, and QoL were evaluated and compared between different reconstruction types. A total of 151 women were included. The flap-based group had higher complication rates of marginal necrosis of incision, while the incidence of capsular contracture was higher in immediate implant group. There was no difference in blood loss, drainage fluid, and other postoperative complications. Several independent factors were associated with increased postoperative complications included diabetic, obese, and reconstruction with flap. There was no significant difference in the disease-free survival rate and overall survival rate between different surgical groups. In terms of cosmetic effect, patients in the tissue expander group were more likely to get a satisfactory postoperative breast appearance. QoL outcomes shown that the tissue expander group has better body image and sexual enjoyment, while there was no significant difference for other QoL domains. In conclusion, different methods of breast reconstruction are safe and feasible for patients with breast cancer, tissue expander implantation following delayed implant breast reconstruction is a more effective treatment on cosmetic and QoL outcomes.

Elevated expression of POLD1 is associated with poor prognosis in breast cancer.

Polymerase δ catalytic subunit gene 1 (POLD1) may serve an important function in the development of tumors. However, its role in breast cancer remains unclear. The aim of the present study was to observe the expression and the function of POLD1 in breast cancer. A total of 84 patients with invasive breast carcinoma were recruited between 2011 and 2013. The expression of POLD1 was detected in paired tumor and adjacent normal tissues. Gene expression level of POLD1 was assessed using reverse transcription quantitative polymerase chain reaction. The protein expression of POLD1 was assessed using western blot analysis. The association between the clinicopathological features of patients with breast cancer and POLD1 expression was analyzed using a χ2 test. Disease-free survival (DFS) was analyzed using Kaplan-Meier method, and Cox regression analysis was performed to investigate clinicopathological significance of POLD1 expression. Additionally, the effects of POLD1 in regulating cell cycle and proliferation of MCF-7 cells were evaluated in vitro. The results demonstrated that gene and protein expression levels of POLD1 were significantly elevated in breast cancer tissues compared with those in adjacent normal tissues. Increased expression of POLD1 was significantly associated with positive lymph node status (P=0.028), histological grade (P=0.025), p53 status (P<0.001) and ki-67 index (P=0.020). Survival analysis demonstrated that increased expression of POLD1 was associated with poor DFS (P=0.033). Additionally, increased expression of POLD1 was associated with shorter DFS at early-stage (P=0.037), late-stage cases (P=0.023) and with the presence of triple-negative tumors (TNBC; P=0.049). Multivariate analysis revealed that POLD1 may be used as an independent prognostic factor in patients with breast cancer. In vitro studies revealed that downregulation of POLD1 suppressed cell cycle progression and proliferation in MCF-7 cells. In conclusion, POLD1 may be considered as a potential prognostic marker for invasive breast carcinoma.

Oncological safety of nipple-sparing mastectomy in young patients with breast cancer compared with conventional mastectomy.

Although nipple-sparing mastectomy (NSM) is being used more frequently, the oncological safety of NSM remains unclear, particularly in young patients (<35 years). The aim of the present study was to compare the rates of local recurrence (LR), disease-free survival (DFS) and overall survival (OS) in young patients with breast cancer who had undergone NSM or conventional mastectomy (CM). The clinicopathological data of young patients with stage 0-IIB breast cancer who had undergone NSM (163 cases) or CM (194 cases) between 2007 and 2016 were retrospectively analyzed. The log-rank test was used to analyze the differences in the LR, DFS and OS rates between the two groups and multivariate analysis was used to analyze the patient prognostic factors for DFS. The median follow-up time was 49 months. Patients who had undergone CM were more likely to exhibit stage II disease (68.4 vs. 58.3%; P=0.015) and positive lymph nodes (45.9 vs. 33.1%; P=0.014). In the NSM group, LR occurred in 7 (4.3%) cases, systemic recurrence in 15 (9.2%) cases and mortality in 9 (5.5%) cases. In the CM group, LR occurred in 6 (3.1%) cases, systemic recurrence in 27 (13.9%) cases and mortality in 15 (7.7%) cases. There were no statistical differences in the LR, DFS and OS rates between the two groups (P>0.05). Following adjustment for clinical stage, the LR and DFS rates between the two groups exhibited no significant differences. Analysis of the prognostic factors demonstrated that clinical stage, lymph node status, estrogen and progesterone receptor status and human epidermal growth factor receptor 2 status were associated with DFS (P<0.05). NSM is safe for young patients with early-stage breast cancer and provides patients with an improved cosmetic outcome. Furthermore, nipple-areola complex preservation does not increase the risk of recurrence.