XRCC5/6 polymorphisms and their interactions with smoking, alcohol consumption, and sleep satisfaction in breast cancer risk: A Chinese multi-center study.

BACKGROUND: X-ray repair cross-complementary 5 (XRCC5) and 6 (XRCC6) are critical for DNA repair. Few studies have assessed their association with breast cancer risk, and related gene-environment interactions remain poorly understood. This study aimed to determine the influence of XRCC5/6 polymorphisms on breast cancer risk, and their interactions with cigarette smoking, alcohol consumption, and sleep satisfaction. METHODS: The study included 1039 patients with breast cancer and 1040 controls. Four single-nucleotide polymorphisms of XRCC5 and two of XRCC6 were genotyped. Information about smoking, alcohol consumption, and sleep satisfaction was collected through questionnaires. Odds ratios (OR) and related 95% confidence intervals (95% CI) were assessed using unconditional logistic regression models. Gene-environment interactions were analyzed using logistic regression with multiplicative interaction models. RESULTS: XRCC5 rs16855458 was associated with increased breast cancer risk in the co-dominant (ptrend  = 0.003) and dominant (CA + AA vs. CC, OR = 1.29, 95% CI = 1.07-1.56, p = 0.008) genetic models after Bonferroni correction. The CG + GG genotype of XRCC6 rs2267437 was associated with an increased risk of estrogen receptor-negative/progesterone receptor-negative (ER-/PR-) breast cancer (CG + GG vs. CC: OR = 1.54, 95% CI = 1.12-2.13, p = 0.008) after Bonferroni correction. Moreover, an antagonistic interaction between XRCC5 rs16855458 and alcohol consumption (pinteraction  = 0.017), and a synergistic interaction between XRCC6 rs2267437 and sleep satisfaction were associated with breast cancer risk (pinteraction  = 0.0497). However, these interactions became insignificant after Bonferroni correction. CONCLUSION: XRCC5 rs16855458 was associated with breast cancer risk, and XRCC6 rs2267437 was associated with the risk of ER-/PR- breast cancer. Breast cancer risk associated with XRCC5 and XRCC6 polymorphisms might vary according to alcohol consumption and sleep satisfaction, respectively, and merit further investigation.

Relationship Between Lifestyle Habits and Health-Related Quality of Life of Recently Diagnosed Breast Cancer Patients: A Comparison Between Younger and Older Women in China.

Objective: The aim of this study was to evaluate the relationship between lifestyle habits and health-related quality of life (HRQoL) among different ages who were initially diagnosed with breast cancer (within the first 2 weeks) and to determine the contribution of lifestyle habits factors on HRQoL. Methods: Patients with breast cancer were recruited from 22 hospitals in 11 provinces or municipalities in northern and eastern China. The Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) was used to measure HRQoL. Chi-square test, ANOVA, and multivariable generalized linear models were conducted to identify the differences in HRQoL between two age groups (age <50 years and ≥50 years) and to evaluate the contribution of lifestyle habits factors on HRQoL of patients with breast cancer. Results: About 1,199 eligible patients with breast cancer were used for analysis. Younger women (aged <50 years) appeared to show lower scores than older women (aged ≥50 years) in HRQoL subscales, including emotional well-being (p = 0.003), functional well-being (p = 0.006), breast cancer subscale (p = 0.038), and FACT-B Total scores (p = 0.028). Tea and alcohol consumption and being very satisfied with sleep and current life were the strongest predictors of higher HRQoL in younger group. Meanwhile, no coffee consumption, frequent participation in physical activities, high sleep satisfaction, and current life satisfaction were the key predictors of higher HRQoL in older women with breast cancer. Conclusion: The relationship of the nine lifestyle habit items with HRQoL differed among younger and older women. The associated variable of low HRQoL can help clinicians take intervention early in order to improve the prognosis of patients with breast cancer.

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

A case-control study on risk factors of breast cancer in Han Chinese women.

This study aimed to investigate risk factors associated with breast cancer among Han Chinese women in northern and eastern China. A matched case-control study involving 1489 patients with breast cancer and 1489 controls was conducted across 21 hospitals in 11 provinces in China, from April 2012 to April 2013. We developed a structured questionnaire to record information from face-to-face interviews with participants. Student's t-tests, Pearson's chi-square tests, and univariate and multivariate conditional logistic regression analyses were used to identify variables with significant differences between the case and control groups. Ten variables were identified (P<0.05): location, economic status, waist-to-hip ratio, menopause, family history of breast cancer, present life satisfaction, sleep satisfaction, milk products, behavior prevention scores, and awareness of breast cancer. We identified a comprehensive range of factors related to breast cancer, among which several manageable factors may contribute to breast cancer prevention. Further prospective studies concerning psychological interventions, sleep regulation, health guidance, and physical exercise are required. A screening model for high-risk populations should be put on the agenda.

Circulating High-Molecular-Weight (HMW) Adiponectin Level Is Related with Breast Cancer Risk Better than Total Adiponectin: A Case-Control Study.

The level of total adiponectin, a mixture of different adiponectin forms, has been reported associated with breast cancer risk with inconsistent results. Whether the different forms play different roles in breast cancer risk prediction is unclear. To examine this, we measured total and high molecular weight (HMW) adiponectin in a case-control study (1167 sets). Higher circulating HMW adiponectin was negatively associated with breast cancer risk after adjusting for menopausal status and family history of breast cancer (P=0.024). We analyzed the relationship between adiponectin and breast cancer risk in 6 subgroups. Higher circulating HMW adiponectin was also negatively associated with breast cancer risk (P=0.020, 0.014, 0.035) in the subgroups of postmenopausal women, negative family history of breast cancer, BMI>=24.0. Total adiponectin was positively associated with breast cancer (P=0.028) in the subgroup of BMI<=24.0. Higher HMW/total adiponectin ratio was negatively associated with breast cancer (P=0.019) in the subgroup of postmenopausal women. Interestingly, in the subgroup of women with family history of breast cancer, higher circulating total and HMW adiponectin were positively associated with breast cancer risk (P=0.034, 0.0116). This study showed different forms of circulating adiponectin levels might play different roles in breast cancer risk. A higher circulating HMW adiponectin is associated with a decreased breast cancer risk, especially in postmenopausal, without family history of breast cancer or BMI>=24.0 subgroups, whereas higher circulating HMW adiponectin levels is a risk factor in women with a family history of breast cancer. Further investigation of different forms of adiponectin on breast cancer risk is needed.

A dual-targeting liposome conjugated with transferrin and arginine-glycine-aspartic acid peptide for glioma-targeting therapy.

The treatment of a brain glioma remains one of the most difficult challenges in oncology. In the present study a delivery system was developed for targeted drug delivery across the blood-brain barrier (BBB) to the brain cancer cells. A cyclic arginine-glycine-aspartic acid (RGD) peptide and transferrin (TF) were utilized as targeting ligands. Cyclic RGD peptides are specific targeting ligands of cancer cells and TFs are ligands that specifically target the BBB and cancer cells. Liposome (LP) was used to conjugate the cyclic RGD and TFs to establish the brain glioma cascade delivery system (RGD/TF-LP). The LPs were prepared by the thin film hydration method and physicochemical characterization was conducted. In vitro cell uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could target endothelial and tumor cells, as well as penetrate the tumor cells to reach the core of the tumor spheroids. The results of the in vivo imaging further demonstrated that the RGD/TF-LP provided the highest brain distribution. As a result, the paclitaxel-loaded RGD/TF-LP presents the best antiproliferative activity against C6 cells and tumor spheroids. In conclusion, the RGD/TF-LP may precisely target brain glioma, which may be valuable for glioma imaging and therapy.

Maintenance treatment of trastuzumab for patients with advanced breast cancer to achieve long term survival: two case reports and literature review.

Molecular subtyping of breast cancer may provide additional prognostic information regarding patient outcome. The epidermal growth factor receptor (HER2) overexpressing breast cancers are designated as HER2-postive (HER2+) breast cancer and carry a particularly unfavorable prognosis. We present two cases of HER2-postive metastatic breast cancer (MBC) who are found to be a challenge to treat, especially due to the occurrence of brain metastasis. Trastuzumab-based therapy improves clinical outcomes, even if the patient has undergone multi-line treatment. These case reports also emphasize the importance of retesting HER2 status because it can be discordance in receptor status between primary and recurrent breast cancer.

Tamoxifen-resistant breast cancer cells possess cancer stem-like cell properties.

BACKGROUND: Cancer stem cells (CSCs) are the cause of cancer recurrence because they are resistant to conventional therapy and contribute to cancer growth and metastasis. Endocrinotherapy is the most common breast cancer therapy and acquired tamoxifen (TAM) resistance is the main reason for endocrinotherapy failure during such therapy. Although acquired resistance to endocrine treatment has been extensively studied, the underlying mechanisms are unclear. We hypothesized that breast CSCs played an important role in TAM-induced resistance during breast cancer therapy. Therefore, we investigated the biological characteristics of TAM-resistant (TAM-R) breast cancer cells. METHODS: Mammosphere formation and tumorigenicity of wild-type (WT) and TAM-R MCF7 cells were tested by a mammosphere assay and mouse tumor xenografts respectively. Stem-cell markers (SOX-2, OCT-4, and CD133) and epithelial-mesenchymal transition (EMT) markers were tested by quantitative real-time (qRT)-PCR. Morphological observation was performed to characterize EMT. RESULTS: After induction of TAM resistance, TAM-R MCF7 cells exhibited increased proliferation in the presence of TAM compared to that of WT MCF7 cells (P < 0.05), indicating enhanced TAM resistance of TAM-R MCF7 cells compared to that of WT MCF7 cells. TAM-R MCF7 cells showed enhanced mammosphere formation and tumorigenicity in nude mice compared to that of WT MCF7 cells (P < 0.01), demonstrating the elevated CSC properties of TAM-R MCF7 cells. Consistently, qRT-PCR revealed that TAM-R MCF7 cells expressed increased mRNA levels of stem cell markers including SOX-2, OCT-4, and CD133, compared to those of WT MCF7 cells (P < 0.05). Morphologically, TAM-R MCF7 cells showed a fibroblastic phenotype, but WT MCF7 cells were epithelial-like. After induction of TAM resistance, qRT-PCR indicated that MCF7 cells expressed increased mRNA levels of Snail, vimentin, and N-cadherin and decreased levels of E-cadherin, which are considered as EMT characteristics (P < 0.05). CONCLUSION: TAM-R MCF7 cells possess CSC characteristics and may be responsible for TAM resistance during breast cancer therapy.

[Effects of high glucose on in vitro invasiveness of human breast cancer cell line MDA-MB-435].

OBJECTIVE: To explore the effects and underlying mechanisms of high glucose on in vitro invasiveness of human breast cancer cell line MDA-MB-435. METHODS: The invasiveness of MDA-MB-435 was determined by Matrigel-coated transwell chambers. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were employed to analyze the cellular expression of matrix metalloproteinase-9/matrix metalloproteinase-2/E-cadherin (MMP-9/MMP-2/E-cadherin) gene/protein. RESULTS: The invasive breast cancer cell numbers of each group (Glu 5.5, 11 and 25 mmol/L) were 50 ± 5, 65 ± 6 and 77 ± 3 respectively. Cellular invasion was dramatically enhanced in the Glu 11 and 25 mmol/L group compared with the 5.5 mmol/L group. The MMP-9/MMP-2 protein expression increased significantly in the Glu 11 and 25 mmol/L groups compared with 5.5 mmol/L group while high glucose (Glu 11 and 25 mmol/L group) down-regulated significantly the E-cadherin mRNA/protein expression. CONCLUSION: High glucose can promote the in vitro invasiveness of human breast cancer cells through the altered expression of MMP-9/MMP-2/E-cadherin.

High risk factors of brain metastases in 295 patients with advanced breast cancer.

BACKGROUND: The incidence of brain metastases in patients with breast cancer is approximately 10% - 16%, and survival after diagnosis of brain metastases is usually short. This study was designed to evaluate the risk factors associated with brain metastases in advanced breast cancer patients, with a view to help predict patient groups with high risk of brain metastases. METHODS: In total, 295 patients with advanced breast cancer were evaluated. All patients were pathologically confirmed and metastatic lesions were confirmed pathologically or by imaging. All patients were examined at least once every 6 months with head CT or MRI. Patients showing symptoms underwent immediate inspection, and brain metastatic lesions were confirmed by head CT and/or MRI. RESULTS: At a median follow-up of 12 months from the occurrence of metastases, brain metastases had occurred in 49 patients (16.6%). In our univariate analysis, variables significantly related to increased risk of brain metastases were hormone receptor-negative tumors, epidermal growth factor receptor 2 (HER2)-positive tumors, and multiple distant metastases. Patients with dominant tumor sites in soft tissue, or defined as Luminal A subtype, tended to have a lower risk of brain metastases than patients with visceral metastases, Luminal B subtype, triple-negative subtype or HER2-enriched subtype tumors. CONCLUSIONS: Our results strongly suggest that factors such as Luminal B, triple-negative, and HER2-enriched subtypes are high risk factors for brain metastases. These data, therefore, provide pivotal clinical evidence towards a comprehensive understanding of the risk factors of brain metastases in advanced breast cancer patients.

Dysregulated expression of dicer and drosha in breast cancer.

Large-scale profiling approaches have revealed global down-regulation of microRNAs (miRNAs) in several human cancer types including breast cancer. Altered expression of Dicer and Drosha, two key enzymes in the miRNA maturation, is believed to be one of the most important mechanisms. By using quantitative real-time RT-PCR (QT-PCR), we examined the expression of Dicer and Drosha in 49 pairs of matched human breast cancer tissues. Decreased expression was observed in 53.1% (Dicer), 51.9% (Drosha) and 75.5% (Dicer plus Drosha) breast cancer tissues. In conclusion, the decreased expression of Dicer and Drosha may play a role in down-regulation of miRNAs in breast cancer.

Enrichment of breast cancer stem cells using a keratinocyte serum-free medium.

BACKGROUND: Keratinocyte serum-free medium (K-SFM) is a defined medium used to support the growth of primary keratinocytes and embryonic stem cell. The aim of this research was to optimize enrichment of breast cancer stem cells (CSCs) using K-SFM. METHODS: A K-SFM was used to enrich CSCs from two breast cancer cell lines and a primary culture of breast cancer. RPMI-1640 supplemented with 10% fetal calf serum (FCS) was used as a control. CSCs were identified with flow cytometry using CD44(+)/CD24(-) as molecular markers. The expression of a variety of CSC markers (Oct-4, ABCG2, Nanog, N-cadherin, and E-cadherin) was analyzed with real-time PCR. RESULTS: Much higher percentage of CSCs was achieved with K-SFM: 17.3% for MCF-7 cells, 17.4% for SKBR-3, and 20.0% for primary breast cancer culture. Less than 1% CSC was achieved using RPMI-1640 supplemented with 10% FCS. In comparison to the CSCs obtained with RPMI-1640, CSCs in the K-SFM expressed higher levels of Oct-4, ABCG2, Nanog and N-cadherin, and lower level of E-cadherin. CONCLUSION: K-SFM is an optimal culture medium to maintain and to enrich breast CSCs.

[Predictive value of (99)Tc(m)-MIBI scintimammography in evaluation of the efficacy of neoadjuvant chemotherapy in patients with operable breast cancer].

OBJECTIVE: To investigate the value of technetium-99m methoxyisobutylisonitrile ((99)Tc(m)-MIBI) imaging in predicting the efficacy of neoadjuvant chemotherapy (NCT) and prognosis in patients with operable breast cancer. METHODS: Sixty five patients with breast cancer underwent (99)Tc(m)-MIBI scintimammography before NCT, and static planar images were taken at 10 min and 180 min after scintimammography. The clearance rate was calculated in each patient, correlation between the clearance rate and efficacy of NCT, and the disease free survival rate were analyzed. RESULTS: The mean clearance rate of 65 patients was (17.4 ± 6.8)%. The efficacy of NCT was 86.2% (CR 4 cases, PR 52 cases, SD 8 cases, and PD 1 case), and the mean clearance rate of patients with good response or poor response of chemotherapy were (15.5 ± 5.0)% and (29.2 ± 3.2)%, respectively. There was a significant difference between the two groups. The average disease free survival rate in the group with low clearance rate was (75.8%, P = 0.046), significantly higher than that in the group with high clearance rate (53.1%). CONCLUSION: Scintimammography of (99)Tc(m)-MIBI may be used to evaluate the efficacy and prognosis of NCT for patients with operable breast cancer.

[Predicative value of 99mTc-MIBI scintimammography in neoadjuvant chemotherapeutic effect of patients with operable breast cancer].

OBJECTIVE: To evaluate the relationship between the clearance rate of technetium-99m methoxyisobutylisonitrile ((99m)Tc-MIBI) in scintimammography and the efficacy of neoadjuvant chemotherapy (NCT) of patients with operable breast cancer. METHODS: Seventy-eight patients with breast cancer underwent (99m)Tc-MIBI scintimammography at pre-NCT. And static planar images were taken at 10 min and 180 min post-scintimammography. The clearance rate was calculated in each patient. And the efficacy of NCT was evaluated after 2 cycles. RESULTS: The clearance rates of patients with a poor or good efficacy of chemotherapy were 24.21% ± 6.38% (n = 14) and 14.13% ± 5.98% (n = 64) respectively. There was significant difference between two groups. And a significant correlation was observed between the efficacy of chemotherapy and the clearance rate of (99m)Tc-MIBI (r = -0.539, P < 0.001). CONCLUSION: The scintimammography of (99m)Tc-MIBI may be employed to evaluate the efficacy of NCT.

[The relationship between 99mTc-MIBI scintimammography of breast cancer and multidrug-resistant proteins].

OBJECTIVE: To evaluate the relationship between the clearance rate of technetium-99m methoxyisobutylisonitrile ((99m)Tc-MIBI) in scintimammography and multidrug-resistant proteins expression in breast cancer tissues. METHODS: Seventy-six patients with breast cancer underwent (99m)Tc-MIBI scintimammography before treatment, and static planar images were taken at 10 min and 180 min after scintimammography. The clearance rate of (99m)Tc-MIBI was calculated in each patient. Immunohistochemical analysis was performed on pathological specimens of the 76 breast tumors to determine the expression of P-glycoprotein (P-gp), glutathione S-transferase Pi (GST-pi) and topoisomerase II (Topo II). RESULTS: The clearance rate was significantly higher in 36 patients with positive P-gp expression when compared with that in 40 patients with negative P-gp expression. There was no significant relationship between GST-pi, Topo II and the clearance rate of (99m)Tc-MIBI. CONCLUSION: The clearance rate of (99m)Tc-MIBI in breast imaging may be used to evaluate the P-gp level in breast cancers.

[Correlation of expression of heparanase to angiogenesis and prognosis of breast cancer].

BACKGROUND & OBJECTIVE: Heparanase is a heparan sulfate proteoglycan cleaving enzyme. It helps to degrade extracellular matrix and basement membrane, promote angiogenesis, and accelerate tumor metastasis. This study was to investigate correlation of heparanase expression to angiogenesis and prognosis of breast cancer. METHODS: Immunohistochemistry was used to detect heparanase and microvessel density (MVD) in 120 specimens of infiltrative ductal breast cancer, and 10 specimens of normal breast tissue. Correlation of heparanase expression to clinicopathologic factors and prognosis of breast cancer were analyzed using Chi-square test, t test, Kaplan-Meier method, and log-rank test. RESULTS: Positive rate of heparanase in breast cancer was 65% (78/120), significantly higher than that in normal breast tissue (0, 0/10) (P< 0.05). MVD in breast cancer was 53.84+/-13.45, significantly higher than that in control group (33.32+/-8.55) (P< 0.01). Expression of heparanase positively correlated with tumor size, histological grade, lymph node metastasis, and clinical stage (P< 0.05) of breast cancer, and negatively correlated with 5-year survival rate (P< 0.05). MVD in heparanase positive group was much higher than that in heparanase negative group (P< 0.05), MVD positively correlated with heparanase expression (r=0.358,P< 0.01). CONCLUSION: Heparanase may promote angiogenesis, and may closely correlate with prognosis of breast cancer.