Chaperone-mediated autophagy degrade Dicer to promote breast cancer metastasis.

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.

Female breast cancer incidence predisposing risk factors identification using nationwide big data: a matched nested case-control study in Taiwan.

BACKGROUND: Breast cancer is an umbrella term referring to a group of biologically and molecularly heterogeneous diseases originating from the breast. Globally, incidences of breast cancer has been increasing dramatically over the past decades. Analyses of multiple clinical "big data" can aid us in clarifying the means of preventing the disease. In addition, predisposing risk factors will be the most important issues if we can confirm their relevance. This study aims to provide an overview of the predisposing factors that contribute to a higher possibility of developing breast cancer and emphasize the signs that we ought to pay more attention to. METHODS: This is a matched nested case-control study. The cohort focused on identifying the eligible risk factors in breast cancer development by data screening (2000-2013) from the Taiwan National Health Insurance Research Database (NHIRD) under approved protocol. A total of 486,069 females were enrolled from a nationwide sampled database, and 3281 females was elligible as breast cancer cohort, 478,574 females who had never diagnosed with breast cancer from 2000 to 2013 were eligible as non-breast cancer controls, and matched to breast cancer cases according to age using a 1:6 ratio. RESULTS: We analyzed 3281 breast cancer cases and 19,686 non-breast cancer controls after an age-matched procedure. The significant predisposing factors associated with breast cancer development including obesity, hyperlipidemia, thyroid cancer and liver cancer. As for patients under the age of 55, gastric cancer does seem to have an impact on the development of breast cancer; compared with their counterparts over the age of 55, endometrial cancer appears to exhibit an evocative effect. CONCLUSIONS: In this nationwide matched nested case-control study, we identified obesity, hyperlipidemia, previous cancers of the thyroid, stomach and liver as risk factors associated with breast cancer. However, the retrospective nature and limited case numbers of certain cancers still difficult to provide robust evidence. Further prospective studies are necessitated to corroborate this finding in order to nip the disease in the bud. TRIAL REGISTRATION: The studies involving human participants were reviewed and approved by the China Medical University Hospital [CMUH104-REC2-115(AR-4)].

Risk of Breast Cancer in Females With Hypothyroidism: A Nationwide, Population-Based, Cohort Study.

OBJECTIVES: The results of studies investigating the relationship between breast cancer and hypothyroidism vary greatly from study to study. In this study, we analyzed a large and reliable, population-based database to gain a better understanding of the correlation. METHODS: This retrospective cohort study analyzed patients with hypothyroidism between January 1, 2000 and December 31, 2012 (hypothyroidism cohort) from the Longitudinal Health Insurance Database 2000 in Taiwan. For each woman with hypothyroidism, 1 woman without a history of breast cancer was randomly selected from the Longitudinal Health Insurance Database 2000 and frequency matched (1:4) with women without hypothyroidism by age and index year of hypothyroidism. The study outcome was the diagnosis of breast cancer during a 12-year follow-up period. RESULTS: In this study, 6665 women with hypothyroidism and 26 660 women without hypothyroidism were identified. The hypothyroidism cohort had a significantly higher risk of breast cancer than the nonhypothyroidism cohort (adjusted hazard ratio [aHR] 1.69 [95% CI, 1.15-2.49]; P = .01), especially in the group aged 40 to 64 years (aHR 2.07 [95% CI, 1.32-3.23]; P = .01). Women in the hypothyroidism cohort taking levothyroxine for a duration ˃588 days showed a significantly decreased risk of breast cancer (aHR 0.37 [95% CI, 0.19-0.71]; P = .003). CONCLUSION: Women with hypothyroidism are at a higher risk of breast cancer than those without hypothyroidism. Levothyroxine may reduce the risk of breast cancer in a woman with hypothyroidism.

Reduction of global 5-hydroxymethylcytosine is a poor prognostic factor in breast cancer patients, especially for an ER/PR-negative subtype.

DNA methylation at the 5 position of cytosine (5 mC) is an epigenetic hallmark in cancer. The 5 mC can be converted to 5-hydroxymethylcytosine (5 hmC) through a ten-eleven-translocation (TET). We investigated the impact of 5 mC, 5 hmC, TET1, and TET2 on tumorigenesis and prognosis of breast cancer. Immunohistochemistry was used to assess the levels of 5 mC, 5 hmC, TET1, and TET2 in the corresponding tumor adjacent normal (n = 309), ductal carcinoma in situ (DCIS, n = 120), and invasive ductal carcinoma (IDC, n = 309) tissues for 309 breast ductal carcinoma patients. 5 mC, 5 hmC, TET1-n, and TET2-n were significantly decreased during DCIS and IDC progression. In IDC, the decrease of 5 hmC was correlated with the cytoplasmic mislocalization of TET1 (p < 0.001) as well as poor disease-specific survival (DSS) (adjusted hazard ratio [AHR] 1.95, p = 0.003) and disease-free survival (DFS) (AHR 1.91, p = 0.006). The combined decrease of 5 mC and 5 hmC was correlated with worse DSS (AHR 2.19, p = 0.008) and DFS (AHR 1.99, p = 0.036). Stratification analysis revealed that the low level of 5 mC was associated with poor DSS (AHR 1.89, p = 0.044) and DFS (AHR 2.02, p = 0.035) for the ER/PR-positive subtype. Conversely, the low level of 5 hmC was associated with worse DSS (AHR 2.77, p = 0.002) and DFS (AHR 2.69, p = 0.006) for the ER/PR-negative subtype. The decreases of 5 mC, 5 hmC, TET1-n, and TET2-n were biomarkers of tumor development. The global reduction of 5 hmC was a poor prognostic factor for IDC, especially for ER/PR-negative subtype.

Lapatinib-mediated cyclooxygenase-2 expression via epidermal growth factor receptor/HuR interaction enhances the aggressiveness of triple-negative breast cancer cells.

Lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) kinase inhibitor, showed clinical benefits in advanced HER2-positive breast cancer patients. Because some triple-negative breast cancers (TNBCs) frequently overexpress EGFR, the antitumor activity of lapatinib in such diseases was also tested. However, the results showed a worse event-free survival rate. It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells. In this study, our results demonstrated that lapatinib facilitated axillary and lung metastases of triple-negative MDA-MB-231 breast cancer cells without affecting their viability, leading to worse survival in orthotopic xenograft mice. The lapatinib-increased motility was attributed by the elevation of EGFR through the downregulation of microRNA-7 and by the subsequent overexpression of cyclooxygenase-2 (COX-2). Strikingly, independent of its kinase activity, the elevated EGFR at least partly stabilized COX-2 expression by enhancing the binding of HuR to COX-2 mRNA. Our results suggest that lapatinib may increase the migration and invasion of MDA-MB-231 cells by upregulating EGFR and COX-2 through the downregulation of microRNA-7, providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib-based treatment. These findings also shed new light on the molecular mechanism of COX-2 mRNA stabilization by EGFR in a kinase-independent manner.

Lapatinib-induced NF-kappaB activation sensitizes triple-negative breast cancer cells to proteasome inhibitors.

INTRODUCTION: Triple-negative breast cancer (TNBC), a subtype of breast cancer with negative expressions of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is frequently diagnosed in younger women and has poor prognosis for disease-free and overall survival. Due to the lack of known oncogenic drivers for TNBC proliferation, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. METHODS: Triple-negative breast cancer cell lines were treated with proteasome inhibitors in combination with lapatinib (a dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor). Their in vitro and in vivo viability was examined by MTT assay, clonogenic analysis, and orthotopic xenograft mice model. Luciferase reporter gene, immunoblot, and RT-qPCR, immunoprecipitation assays were used to investigate the molecular mechanisms of action. RESULTS: Our data showed that nuclear factor (NF)-κB activation was elicited by lapatinib, independent of EGFR/HER2 inhibition, in TNBCs. Lapatinib-induced constitutive activation of NF-κB involved Src family kinase (SFK)-dependent p65 and IκBα phosphorylations, and rendered these cells more vulnerable to NF-κB inhibition by p65 small hairpin RNA. Lapatinib but not other EGFR inhibitors synergized the anti-tumor activity of proteasome inhibitors both in vitro and in vivo. Our results suggest that treatment of TNBCs with lapatinib may enhance their oncogene addiction to NF-κB, and thus augment the anti-tumor activity of proteasome inhibitors. CONCLUSIONS: These findings suggest that combination therapy of a proteasome inhibitor with lapatinib may benefit TNBC patients.

Clinical and pathologic risk factors of tumor recurrence in patients with node-negative early breast cancer after mastectomy.

BACKGROUND AND OBJECTIVES: Patients with node-negative breast cancer (NNBC) usually have a good prognosis, but tumor recurrence still compromises survival. In this study, we sought to identify clinical and pathologic factors that predict recurrence. METHODS: A total of 716 patients who were proved with pT1-2N0M0 breast cancer between 2005 and 2009 were enrolled in this study. RESULTS: Forty-seven of the 716 patients developed tumor recurrence during the 47.0 months of median follow-up. The significant risk factors of recurrence were lymphovascular invasion (LVI) (hazard ratio [HR] = 4.60, 95% CI. 2.32-9.10) and Nottingham grade 3 (HR = 4.99, 95% CI. 1.06-23.48); adjuvant radiotherapy (HR = 0.35, 95% CI. 0.14-0.92) prevented tumor recurrence. Furthermore, we investigate the therapeutic impact of adjuvant chemotherapy and radiotherapy on patients with LVI and Nottingham grade 3. The adverse effect of LVI and grade 3 can be abrogated by adjuvant radiotherapy in recurrence-free survival (RFS) (LVI((+)) radiotherapy((+)) , no recurrence; grade 3((+)) radiotherapy((+)) , HR = 0.82, 95% CI. 0.18-3.70). However, adjuvant chemotherapy did not. CONCLUSIONS: LVI and Nottingham grade 3 were the independent risk factors predicting tumor recurrence for patients with NNBC. Adjuvant radiotherapy might be considered in NNBC patients with these unfavorable factors to improve the RFS.

Hepatoma-derived growth factor regulates breast cancer cell invasion by modulating epithelial--mesenchymal transition.

Hepatoma-derived growth factor (HDGF) participates in tumourigenesis but its role in breast cancer is unclear. We set out to elucidate the expression profile and function of HDGF during breast carcinogenesis. Immunoblot and immunohistochemical studies revealed elevated HDGF expression in human breast cancer cell lines and tissues. Nuclear HDGF labelling index was positively correlated with tumour grade, stage and proliferation index, but negatively correlated with survival rate in breast cancer patients. HDGF over-expression was associated with lymph node metastasis and represented an independent prognostic factor for tumour recurrence. Gene transfer studies were performed to elucidate the influence of cellular HDGF level on the malignant behaviour and epithelial-mesenchymal transition (EMT) of breast cancer cells. Adenovirus-mediated HDGF over-expression stimulated the invasiveness and colony formation of MCF-7 cells. Moreover, HDGF over-expression promoted breast cancer cell EMT by E-cadherin down-regulation and vimentin up-regulation. Conversely, HDGF knockdown by RNA interference in MDA-MB-231 cells attenuated the malignant behaviour and elicited EMT reversal by enhancing E-cadherin expression while depleting vimentin expression. Because HDGF is a secreted protein, we evaluated the cellular function of recombinant HDGF and found that exogenously supplied HDGF enhanced the invasiveness of breast cancer cells by down-regulating E-cadherin and up-regulating vimentin at transcriptional and translational levels. In contrast, blockade of HDGF secretion with an HDGF antibody inhibited the malignant behaviours and EMT. Finally, exogenous HDGF partially reversed benzyl isothiocyanate (BITC)-induced EMT suppression. HDGF over-expression may exert a prognostic role for tumour metastasis and recurrence in breast cancer by modulating EMT. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Recurrence after skin-sparing mastectomy and immediate transverse rectus abdominis musculocutaneous flap reconstruction for invasive breast cancer.

BACKGROUND: The aim of this study was to evaluate the recurrence pattern after skin-sparing mastectomy (SSM) and immediate breast reconstruction (IBR) using transverse rectus abdominis musculocutaneous (TRAM) flap in patients with invasive breast cancer. METHODS: From 1995 to 2010, patients with invasive breast cancer who underwent SSM followed by IBR using TRAM flap were retrospectively reviewed. The pattern of the first recurrence event was recorded. RESULTS: We identified 249 consecutive patients with invasive breast cancer, two-thirds of whom (67.1%) were diagnosed with stage II or stage III disease. During a median follow-up period of 53 months, three (1.2%) local, 13 (5.2%) regional, 34 (13.7%) distant, and five (2.0%) concurrent locoregional and distant recurrences were observed. The median time to recurrences was 26 months (range, 2 to 70 months) for all recurrences, 23 months (range, 2 to 64 months) for locoregional recurrences, and 26 months (range, 8 to 70 months) for distant recurrences. All local recurrent lesions were detectable by careful physical examination, and detection of local recurrence suggested the presence of distant metastasis (60.0%). In contrast to distant metastasis, the risk of locoregional recurrence did not increase significantly with an increase in disease stage. The 5-year overall, locoregional relapse-free, and distant relapse-free survival rates were 89.7%, 90.8%, and 81.6%, respectively. CONCLUSIONS: SSM followed by immediate reconstruction using TRAM flap is an oncologically safe procedure even in patients with advanced-stage disease. Detection of local recurrence is crucial and can be aided by a thorough physical examination.

Psychological Well-Being Increment as Post-Traumatic Growth in Women with Breast Cancer: A Controlled Comparison Design Using Propensity Score Matching.

The aim of this study was to confirm post-traumatic growth with respect to the psychological well-being of women with breast cancer compared to women without disease. Propensity score was used to match the two groups according to age, religious beliefs, education level, monthly income, and marital status. A psychological well-being scale with six factors was used, including positive relations with others (PR), autonomy (AU), environmental mastery (EM), personal growth (PG), purpose in life (PL), and self-acceptance (SA). A total 178 women with vs. 178 women without breast cancer were compared by matching with propensity scores, using factorial invariance tests to reduce measurement errors. The results showed that women with breast cancer had significantly higher psychological well-being for all the six factors (Δχ2 = 37.37, p < 0.001) and higher variability in terms of PR, AU, and PL than women without breast cancer (Δχ2 = 45.94, p < 0.001). Furthermore, women with breast cancer exhibited a significantly higher association between PG and PL and a significantly lower association between PG and EM than women without breast cancer (Δχ2 = 44.49, p < 0.001). This implies that psychological well-being could assess broader and more subtle post-traumatic growth in women with breast cancer and that growth was more associated with internal life value than with external environmental control.

Association between Breast Cancer and Second Primary Lung Cancer among the Female Population in Taiwan: A Nationwide Population-Based Cohort Study.

PURPOSE: A special association between breast cancer and second primary lung cancer in Taiwanese women has been discovered not only in clinical practice, but also in a large population-based study. We hereby investigate the association between breast cancer and second primary lung cancer in Taiwanese women. METHODS: This study was conducted from the National Health Insurance Research Database (NHIRD) from Taiwan National Health Insurance (NHI). Patients older than 18 years old and hospitalized with a first diagnosis of breast cancer during 2000 to 2012 were enrolled in the breast cancer group. Patients who were cancer free were frequency-matched with the breast cancer group by age (every five-year span) and index year. The ratio of breast cancer group to non-breast cancer group was 1:4. The event as the outcome in this study was lung cancer. The comorbidities viewed as important confounding factors included coronary artery disease, stroke, hypertension, diabetes, chronic obstructive pulmonary disease, hyperlipidemia, tuberculosis, chronic kidney disease, and chronic liver disease and cirrhosis. We estimated the hazard ratios (HRs), adjusted hazard ratios (aHRs), and 95% confidence intervals (CIs) for risk of lung cancer in the breast cancer group and non-breast cancer group using Cox proportional hazard models. Sensitivity analysis was also done using propensity score matching. All of the statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc., Cary, NC). RESULTS: There were 94,451 breast cancer patients in the breast cancer group and 377,804 patients in the non-breast cancer group in this study. After being stratified by age, urbanization level, and comorbidities, the patients with breast cancer had a significantly higher risk of lung cancer compared with the patients without breast cancer, particularly for those who aged between 20 and 49 years (aHR = 2.10, 95% CI = 1.71-2.58), 50 and 64 years (aHR = 1.35, 95% CI = 1.15-1.58), and those without any comorbidities (aHR = 1.92, 95% CI = 1.64-2.23). CONCLUSION: Patients with breast cancer had a significantly higher risk of developing second primary lung cancer compared with patients without breast cancer, particularly in younger groups and in those without any comorbidities. The special association may be attributed to some potential risk factors such as genetic susceptibility and long-term exposure to PM2.5, and is supposed to increase public awareness. Further studies are necessary given the fact that inherited genotypes, different subtypes of breast cancer and lung cancer, and other unrecognized etiologies may play vital roles in both cancers' development.

Risk Role of Breast Cancer in Association with Human Papilloma Virus among Female Population in Taiwan: A Nationwide Population-Based Cohort Study.

PURPOSE: We analyzed data from the National Health Insurance Research Database (NHIRD) in Taiwan, collected information regarding human papillomavirus (HPV) and breast cancer prevalence, and explored the association between HPV infection and the risk of breast carcinoma. METHODS: We included the NHIRD data of 30,936 insured patients aged 20 years an older without breast cancer prior to the index date (date of HPV diagnosis) and matched each patient with a reference subject according to age, comorbidities, and index year (1:1 ratio). We calculated the incidence rates of breast cancer in the cohorts, age groups, and comorbidity groups, as well as the relative risk of breast cancer stratified by age and comorbidity in the HPV and non-HPV groups. RESULTS: The patients with and without HPV had incidence rates of 12.5 and 9.81 per 10,000 person years, respectively. The risk of breast cancer for the 50-64 and ≥65 age groups was 1.67 and 1.36 times higher than that in patients younger than 49 years, respectively, and hypertension, chronic obstructive pulmonary disease, and diabetes mellitus were significant risk factors for breast cancer. The HPV group had a higher risk of developing breast cancer than the non-HPV group, regardless of age group and the presence or absence of comorbidities. Patients with HPV in the 50-64 age group were 1.39 times more likely to develop breast cancer than patients of the same age without HPV. CONCLUSION: Patients older than 49 were more likely to develop breast cancer, and patients with HPV had a higher likelihood of developing breast cancer, regardless of age and the presence or absence of comorbidities. HPV likely plays a causal role in breast cancer.

Dicer-mediated miR-200b expression contributes to cell migratory/invasive abilities and cancer stem cells properties of breast cancer cells.

Distant metastasis is the leading cause of death in patients with breast cancer. Despite considerable treatment advances, the clinical outcomes of patients with metastatic breast cancer remain poor. CSCs can self-renew, enhancing cancer progression and metastasis. Dicer, a microRNA (miRNA) processing-related enzyme, is required for miRNA maturation. Imbalanced Dicer expression may be pivotal in cancer progression. However, whether and how Dicer affects the stemness of metastatic breast cancer cells remains unclear. Here, we hypothesized that Dicer regulates the migration, invasion, and stemness of breast cancer cells. We established highly invasive cell lines (MCF-7/I-3 and MDA-MB-231/I-3) and observed that Dicer expression was conspicuously lower in the highly invasive cells than in the parental cells. The silencing of Dicer significantly enhanced the cell migratory/invasive abilities and CSCs properties of the breast cancer cells. Conversely, the overexpression of Dicer in the highly invasive cells reduced their migration, invasion, and CSCs properties. Our bioinformatics analyses demonstrated that low Dicer levels were correlated with increased breast cancer risk. Suppression of Dicer inhibited miR-200b expression, whereas miR-200b suppression recovered Dicer knockdown-induced migration, invasion, and cancer stem cells (CSCs) properties of the breast cancer cells. Thus, our findings reveal that Dicer is a crucial regulator of the migration, invasion, and CSCs properties of breast cancer cells and is significantly associated with poor survival in patients with breast cancer.

Association of Insomnia, Depressive Disorders, and Mood Disorders as Risk Factors With Breast Cancer: A Nationwide Population-Based Cohort Study of 232,108 Women in Taiwan.

BACKGROUND: Insomnia, depressive disorders, and to a more general view, mood disorders are raising people's concerns and causing disability of life. Herein, we try to seek the association of such illnesses with subsequent breast cancer. METHODS: This population-based, retrospective cohort study used data from the Taiwan National Health Insurance Research Database. This study included 232,108 women diagnosed with insomnia, depressive disorders, and mood disorders from January 1, 2000 to December 31, 2013. Physician diagnosed insomnia, depressive disorders, or mood disorders using outpatient and inpatient records before diagnosis of breast cancer. Cox proportional hazards regression analysis is adjusted for women with insomnia, depressive disorders, mood disorders, and other factors like insured amount, urbanization, and comorbidities such as having subsequent breast cancer. RESULTS: Sleep medication was associated with a significantly increased incidence rate of breast cancer (aHR = 1.23 (95% CI = 1.13, 1.35), p < 0.001). Insomnia was associated with significant increased hazard of breast cancer (aHR = 1.16 (95% CI = 1.07, 1.27), p < 0.001). Annual insured amount >20,000 (TWD), high urbanization area, and hyperlipidemia were associated with increased hazard of breast cancer (aHR = 1.13 (95% CI = 1.01, 1.27), p = 0.04; aHR = 1.41 (95% CI = 1.17, 1.71), p < 0.001; aHR = 1.14 995% CI = 1.02, 1.29), p = 0.02, respectively). There was a positive correlation between depressive disorders and increased incidence rate of breast cancer but not statistically significant (aHR = 1.11 (95% CI = 0.99, 1.25), p = 0.08). Mood disorders were not associated with increased hazard (aHR = 1.11 (95% CI = 0.91, 1.34), p = 0.31). CONCLUSION: In this study, women with insomnia had increased risk of breast cancer, particularly those in high urbanization or with high insured amounts. Sleep medication (benzodiazepine (BZD) or non-BZD) and hyperlipidemia were independently associated with a higher hazard ratio of breast cancer. Insomnia along with sleep medication did not yield more hazards than each alone. Mood disorders appeared to be not associated with subsequent breast cancer. However, depressive disorders, the subgroups of mood disorders, could possibly increase the incidence rate of breast cancer though not statistically significant.

The association between air pollution level and breast cancer risk in Taiwan.

ABSTRACT: Breast cancer has the highest incidence of cancer among women in Taiwan, and air pollutants have been documented to have multiple adverse effects on human health. There is no relevant data, there has been no research in Taiwan to discuss the relevance of air pollutants to breast cancer, and evidence is sparse and inconclusive.Air quality data used in this study was collected from the 78 air quality monitoring stations situated in 74 municipalities in Taiwan during 2000 to 2011. The daily measurements taken at each monitoring station represented the level of exposure for each participant residing in that zone. The air pollution concentration is partitioned based on the concentration level in Quartile. We calculate the annual average air pollutants concentration (CO, NO, NO2, PM2.5, THC, and CH4) and the long-term average exposure levels of these pollutants until diagnosis of breast cancer, ending the study period for each individual.Patients who were living in areas with the highest air pollutants concentration (Quartile 4) had the most people diagnosed with breast cancer (CO:1.47%, NO:1.41%, NO2:1.63%, PM2.5:0.91%, THC:1.53%, CH4:2.33%). The patients who were exposed to Quartile 1 level of CO, NO, and NO2 concentration were the oldest, and other patients who were exposed to Quartile 4 level of CO, NO, and NO2 concentration were living in the areas of highest urbanization. Participants exposed to Quartile 4 level concentrations of air pollutants were associated with highest hazards ratios for breast cancer incidences.Most participants who were exposed to the high concentration of air pollutants (CO, THC and CH4) had a significantly higher risk of breast cancer. If we can improve air pollution in the environment, we can reduce the incidence of breast cancer and save precious medical resources.

ERα determines the chemo-resistant function of mutant p53 involving the switch between lincRNA-p21 and DDB2 expressions.

Mutant p53 (mutp53) commonly loses its DNA binding affinity to p53 response elements (p53REs) and fails to induce apoptosis fully. However, the p53 mutation does not predict chemoresistance in all subtypes of breast cancers, and the critical determinants remain to be identified. In this study, mutp53 was found to mediate chemotherapy-induced long intergenic noncoding RNA-p21 (lincRNA-p21) expression by targeting the G-quadruplex structure rather than the p53RE on its promoter to promote chemosensitivity. However, estrogen receptor alpha (ERα) suppressed mutp53-mediated lincRNA-p21 expression by hijacking mutp53 to upregulate damaged DNA binding protein 2 (DDB2) transcription for subsequent DNA repair and chemoresistance. Levels of lincRNA-p21 positively correlated with the clinical responses of breast cancer patients to neoadjuvant chemotherapy and had an inverse correlation with the ER status and DDB2 level. In contrast, the carboplatin-induced DDB2 expression was higher in ER-positive breast tumor tissues. These results demonstrated that ER status determines the oncogenic function of mutp53 in chemoresistance by switching its target gene preference from lincRNA-p21 to DDB2 and suggest that induction of lincRNA-p21 and targeting DDB2 would be effective strategies to increase the chemosensitivity of mutp53 breast cancer patients.

Is hepatectomy beneficial in the treatment of multinodular hepatocellular carcinoma?

BACKGROUND/PURPOSE: Hepatectomy remains the standard treatment for primary hepatocellular carcinoma (HCC). However, its role in the treatment of multinodular HCC (MNHCC) is unknown. METHODS: The study consisted of 599 patients undergoing curative hepatic resection for HCC between October 1990 and June 2006, in which 112 patients had MNHCC (tumor number > or = 2). The type of MNHCC was classified into: A, nodules involving one or two adjoining segments; B, large tumor with satellite nodules involving three or more segments; C, three or fewer nodules that are scattered in remote segments; and D, more than three separate tumors. Univariate and multivariate analyses were used to identify the prognostic factors related to postoperative survival. During the same period of time, and from our database of 178 patients with pathologically proven MNHCC who were undergoing nonsurgical multidisciplinary therapy, 48 patients with serum albumin level > or = 3.5 g/dL, total bilirubin < 2 mg/dL, tumor number < or = 3, and tumor size < or = 5 cm were compared with 38 patients with the same condition treated with hepatectomy, in which 16 received one-block resection and 22 underwent multiple-site resection. RESULTS: The overall 1-, 3- and 5-year survival rates for patients with single-tumor HCC and MNHCC were 88.0%, 69.2% and 58.4%, and 86.1%, 55.5% and 29.9%, respectively (p < 0.001). Alpha-fetoprotein > 400 ng/mL, total tumor size > 5 cm, largest tumor size > 5 cm, total tumor number > 3, microvascular invasion, non-A type MNHCC and multiple-site resection were poor prognostic factors for MNHCC in the hepatectomy group. Multivariate analysis revealed that only multiple-site hepatic resection was an independent adverse factor related to postoperative survival. In addition, patients who underwent one-block resection had significantly better survival compared with the nonsurgical group (p = 0.0016), but the multiple-site resection subgroup did not. CONCLUSION: The prognosis of MNHCC is poor in comparison with that of single-nodular HCC. Hepatectomy is the treatment of choice if the tumors can be removed by one-block resection and liver function reserve is acceptable.

Extracellular Matrix-receptor Interaction Signaling Genes Associated with Inferior Breast Cancer Survival.

BACKGROUND/AIM: Breast cancer is a common type of cancer in women, and metastasis frequently leads to therapy failure. Using next-generation sequencing (NGS), we aspired to identify the optimal differentially expressed genes (DEGs) for use as prognostic biomarkers for breast cancer. MATERIALS AND METHODS: NGS was used to determine transcriptome profiles in breast cancer tissues and their corresponding adjacent normal tissues from three patients with breast cancer. RESULTS: Herein, 15 DEGs (fold change >4 and <0.25) involved in extracellular matrix (ECM)-receptor interaction signaling were identified through NGS. Among them, our data indicated that high HMMR expression levels were correlated with a poor pathological stage (p<0.001) and large tumor size (p<0.001), whereas high COL6A6 and Reelin (RELN) expression levels were significantly correlated with an early pathological stage (COL6A6: p=0.003 and RELN: p<0.001). Multivariate analysis revealed that high HMMR and SDC1 expression levels were significantly correlated with poor overall survival (OS; HMMR: adjusted hazard ratio [aHR] 1.93, 95% confidence interval [CI]=1.10-3.41, p=0.023; SDC1: [aHR] 2.47, 95%CI=1.28-4.77, p=0.007) for breast cancer. Combined, the effects of HMMR and SDC1 showed a significant correlation with poor OS for patients with breast cancer (high expression for both HMMR and SDC1: [aHR] 3.29, 95%CI=1.52-7.12, p=0.003). CONCLUSION: These findings suggest that HMMR and SDC1 involved in the ECM-receptor interaction signaling pathway could act as effective independent prognostic biomarkers for breast ductal carcinoma.

High snail expression predicts a poor prognosis in breast invasive ductal carcinoma patients with HER2/EGFR-positive subtypes.

BACKGROUND: High Snail expression is known as a poor prognostic factor in breast cancer. However, its prognostic impact for breast cancer with different molecular subtypes is still controversial. METHODS: Snail expression was examined by immunohistochemistry in tissue microarray slides of 85 corresponding tumor-adjacent normal (CTAN) and 247 breast invasive ductal carcinoma (IDC) tissues. Multivariable Cox regression analysis was used to assess the impact of Snail expression on survival rate by different molecular subtypes of breast IDC patients. RESULTS: The level of Snail expression in IDC tumor tissues was significantly higher than that in CTAN tissues. Moreover, high Snail expression had direct impacts on poor disease specific survival (DSS) and disease-free survival (DFS) in breast IDC patients with human epidermal growth factor receptor 2 (HER2)-positive and human epidermal growth factor receptor (EGFR)-positive statuses as well as the HER2 intrinsic subtype. Additionally, breast IDC patients with a combination of three prognostic factors, including high Snail expression and HER2-positive and EGFR-positive statuses, had much poor DSS and DFS with a statistically significant linear trend. CONCLUSION: High Snail expression could predict a poor prognosis for breast IDC patients with HER2/EGFR-positive subtypes.