Gamma secretase inhibitor enhances sensitivity to doxorubicin in MDA-MB-231 cells.

Deregulated expression of molecular of the Notch signaling pathway is observed in malignant tumor. Notch signaling pathway is activated by a series of catalytic cleavage of the Notch receptor by gamma secretase. Gamma secretase inhibitor (GSI) have demonstrated clinical activity in patients with solid tumor. Triple negative breast cancer (TNBC) is related to poor prognosis and a high probability of lung and brain metastases. As first line therapy for TNBC, doxorubicin is partially effective in TNBC control. An understanding of the mechanisms for enhancing sensitivity to doxorubicin would be significant for future drug development. We hypothesized that a combination of cytotoxic chemotherapy doxorubicin to inhibit cell proliferation, together with GSI, would result in more effective outcome than either monotherapy alone. We treated MDA-MB-231 cell lines with doxorubicin and evaluated the monotherapy efficacy and in combination with GSI in both vitro and vivo. GSI-induced proliferation inhibition and apoptosis was achieved with an induction of PTEN and pro-apoptotic protein Bax expression and suppression of Notch-1, HES-1, CyclinD1 and anti-apoptotic protein Bcl-2. These results indicate that MDA-MB-231 cells are susceptible to a GSI, whether alone or in combination with doxorubicin, are correlated with changing of some surrogate marker. This study demonstrates practicability of combined use of GSI and doxorubicin, and together these results encourage new therapeutic method in triple negative breast cancer.

On the status and comparison of glucose intolerance in female breast cancer patients at initial diagnosis and during chemotherapy through an oral glucose tolerance test.

AIMS: This study is to estimate the status and comparison of glucose intolerance in female breast cancer patients at initial diagnosis and during chemotherapy through an oral glucose tolerance test (OGTT), as well as to learn the effect of chemotherapy on the glucose metabolism of breast cancer patients. METHODS: All the 79 breast cancer patients at initial diagnosis, with the mean age of 53.2 years, and 96 breast cancer patients before the 5th or 6th cycle of chemotherapy, with the mean age of 51.5 years, participated in the study from December 2012 to October 2013. After an overnight fast, participants underwent OGTT test, and fasting and 2-hour glucose levels were measured to identify undiagnosed diabetes and prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance) in them. Previously diagnosed diabetes among the female breast cancer patients was determined on the self-report and the medical record. RESULTS: The overall incidences of total normal glucose tolerance, prediabetes, diabetes in female breast cancer patients at initial diagnosis and during chemotherapy were 24.1% and 38.5% (p<0.05), 50.6% and 28.1% (p<0.05), and 25.3% and 33.3% (p>0.05), respectively, and the differences of normal glucose tolerance and prediabetes instead of diabetes between the two groups were statistically significant. About 84% of the total diabetes and prediabetes in the female breast cancer patients at initial diagnosis and 79.7% of those during chemotherapy need to be diagnosed with OGTT. CONCLUSIONS: Breast cancer patients have high incidences of diabetes and prediabetes. After chemotherapy even with steroids, some breast cancer patients with abnormal glucose metabolism may even become normal. Isolated hyperglycemia 2 hours after glucose loading is common, and OGTT should be made for breast cancer patients at initial diagnosis and during chemotherapy.

Discordance and clinical significance of ER, PR, and HER2 status between primary breast cancer and synchronous axillary lymph node metastasis.

Discordance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status between primary breast cancer, metastatic lesion and synchronous axillary lymph node metastasis has been reported in the series studies. Systemic treatment of primary invasive breast cancer patients with synchronous axillary metastasis is currently based on the biomarker characteristics of the primary tumor; however, hormone receptors and HER2 status may change throughout tumor progression from the primary tumor to the synchronous axillary metastasis. As local metastasis, the synchronous axillary lymph node metastasis may represent the potentially metastatic breast cancer cells much better than the primary tumor. Hence, the determination of hormone receptors and HER2 status should be routinely performed in synchronous axillary nodal metastasis, together with primary tumor, to guide therapy management and evaluate the recurrent risk of primary invasive breast cancer patients with synchronous axillary nodal metastasis, which may even change the postoperative risk categories (St. Gallen consensus) of breast cancer in these patients. This article will review the studies on the discordance and clinical significance of ER, PR, and HER2 receptor status between primary breast cancer and synchronous axillary lymph node metastasis.

Clinicopathologic features of breast cancer patients with type 2 diabetes mellitus in southwest of China.

The aim of this study was to study the prevalence and clinicopathologic features of breast cancer patients with type 2 diabetes mellitus in southwest of China for providing clinical guidance and prognosis appreciation for these patients. Through a case-control study of 3,381 primary breast cancer patients initially diagnosed from January 2007 to May 2013, one case group (164 female breast cancer patients with type 2 diabetes) and two control groups (first control group consists of 328 randomly selected nondiabetic breast cancer patients and second control group consists of 279 nondiabetic breast cancer patients without diabetes-related diseases such as cardiovascular or cerebrovascular diseases) were selected. The clinicopathological features between them were statistically analyzed. (1) Of 3,381 primary breast cancer patients with the average age of 50.5, ranging from 21 to 97 years of age, 164 (4.9 %) cases (with the average age of 60.7) suffered diabetes (previously diagnosed diabetes). (2) The differences of clinicopathologic features between the case group and first control group (with the average age of 61.5) were the ratio of hypertension (41.5 vs 26.1 %, P = 0.001) and axillary lymph node metastasis (51.1 vs 38.1 %, P = 0.046); and the differences of clinicopathologic features between the case group and second control group (with the average age of 64.3) were axillary lymph node metastasis (51.1 vs 35.8 %, P = 0.017), tumor size (≥ T2: 62.3 vs 53.1 %, P = 0.019) and p53 expression (51.0 vs 62.7 %, P = 0.018). No statistical significances (P > 0.05) of histological type, histological grade, or the expressions of estrogen receptor (ER), progesterone receptor, human epidermal growth factor 2 (HER2) and Ki67 were found between them. (3) The clinicopathologic features of ER-positive and ER-negative patients in each group were as follows: (1) In the case group, the ER-negative patients have more advanced tumor histological grade (G3, 19.0 vs 2.8 %, P = 0.012), more positive expression of Her-2 (16.9 vs 8.1 %, P = 0.029) and more axillary lymph node metastasis (63.3 vs 44.4 %, P = 0.048). (2) In the first control group, the same results with tumor histological grade (G3, 15.6 vs 6.2 %, P = 0.025) and positive expression of Her-2 (16.7 vs 4.3 %, P = 0.001), and more positive expression of Ki67 (65.1 vs 52.0 %, P < 0.001) were found. (3) In the second control group, the ER-negative patients have more positive expression of Ki67 (70.5 vs 55.7 %, P = 0.009) and fewer family history of malignancy (1.9 vs 10.0 %, P = 0.013). Diabetes has a high incidence in breast cancer patients and is more common with postmenopausal patients. It is suggested that initially diagnosed breast cancer patients should undertake oral glucose tolerance test screening for occult diabetes and prediabetes. More concerns should be put onto diabetic patients with breast cancer.

Incidences of diabetes and prediabetes among female adult breast cancer patients after systemic treatment.

Patients with cancer frequently show glucose intolerance. This study is to estimate the status of total diabetes and prediabetes in breast cancer patients after systemic treatment through an oral glucose tolerance test (OGTT) in China. All the 119 breast cancer patients more than 3 months after systemic treatment with surgery and chemotherapy participated in the study. All the patients without the diagnosis of diabetes underwent OGTT, and fasting and 2-h glucose levels were measured to identify undiagnosed diabetes and prediabetes. Previously diagnosed diabetes were determined on the self-report and the medical record. Of the 119 breast cancer patients, with the median age of 50.1 years and the mean age of about 48 years when they were initially diagnosed with breast cancer, which showed the similar characters of China and Asia breast cancer patients, the overall incidences of total diabetes and prediabetes were 21.8 and 43.7 %, respectively. About 80 % of the diabetes were previously undiagnosed. About 80.0 % of the cases of undiagnosed diabetes and prediabetes met the criteria for elevated 2-h plasma glucose levels through OGTT but not the criteria for elevated fasting glucose levels. Our study firstly documents high incidences of previously undiagnosed diabetes and prediabetes in breast cancer patients during follow-up after systemic treatment through OGTT, indicating that greater diabetes screening, especially through OGTT, prevention, and treatment strategies among breast cancer patients, after systemic treatment for these patients is needed.

CHEK2 1100delC variant and breast cancer risk in Caucasians: a meta-analysis based on 25 studies with 29,154 cases and 37,064 controls.

Links between the CHEK2 1100delC heterozygote and breast cancer risk have been extensively explored. However, both positive and negative associations with this variant have been reported in individual studies. For a detailed assessment of the CHEK2 1100delC heterozygote and breast cancer risk, relevant studies published as recently as May 2012 were identified using PUBMED and EMBASE and selected using a priori defined criteria. The strength of the relationship between the CHEK2 1100delC variant and breast cancer risks was assessed by odds ratios (ORs) under the fixed effects model. A total of 29,154 cases and 37,064 controls from 25 case-control studies were identified in this meta-analysis. The CHEK2 1100delC heterozygote was more frequently detected in cases than in controls (1.34% versus 0.44%). A significant association was found between CHEK2 1100delC heterozygote and breast cancer risk (OR=2.75, 95% CI: [2.25, 3.36]). The ORs and CIs were 2.33 (95% CI: [1.79, 3.05]), 3.72 (95% CI: [2.61, 5.31]) and 2.78 (95% CI: [2.28, 3.39]) respectively in unselected, family, early-onset breast cancer subgroups. The CHEK2 1100delC variant could be a potential factor for increased breast cancer risk in Caucasians. However, more consideration is needed in order to apply it to allele screening or other clinical work.

Diagnosis prevention and treatment for PICC-related upper extremity deep vein thrombosis in breast cancer patients.

AIM: To study the incidence, diagnosis, prevention and treatment of peripherally inserted central catheter (PICC)-related upper extremity deep vein thrombosis (DVT) in breast cancer patients using a PICC catheter for chemotherapy. METHODS: The data of the incidence, diagnosis and treatment of PICC-related upper extremity DVT in 187 breast cancer patients using a PICC catheter for chemotherapy, from August 2009 to July 2011 were retrospectively analyzed. RESULTS: In total 188 PICC were inserted between August 2009 and July 2011 and followed up for a total of 14 399 catheter-days (median placement, 76.6 days; range, 1 to 170 days). Four (2.1%) of 188 PICC were removed as a result of PICC-related upper extremity DVT in 14 to 112 catheter-days, at a rate of 0.28/1000 catheter-days. CONCLUSION: The use of PICCs in breast cancer patients for chemotherapy is safe and effective. However, some patients may develop catheter-related upper extremity DVT. In order to minimize complications, we should pay attention to its early symptoms and signs, as well as the timely removal of the catheter and appropriate anti-coagulant treatment.

Effects of antisense oligonucleotides of PKC-alpha on proliferation and apoptosis of HepG2 in vitro.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies in China. The long-term survival rate of patients with HCC after prevention and management remains unsatisfactory. In order to provide a novel strategy to cure HCC, we investigated the effects of antisense oligonucleotides of PKC-alpha on proliferation and apoptosis of human hepatoma cell line HepG2 in vitro. METHODS: The human hepatocellular carcinoma cell line HepG2 was cultured and subcultured in RPMI1640 medium in vitro. PKC-alpha antisense oligonucleotides(asODN) of different concentrations with a random sequence as a control were transfected into HepG2 cells by lipofectin(LP). The cell growth index (GI) and the clone formation rate of HepG2 were detected by MTT colorimetric assay and soft agar assay, respectively. The apoptosis rate of HepG2 treated with PKC-alpha asODN was assayed by flow cytometry(FCM). The results were analyzed by SPSS 10.0 software. RESULTS: The GI of HepG2 transfected by PKC-alpha asODN with concentrations ranging from 0.10 micromol to 1.00 micromol were lower significantly than those of control groups (P<0.05). The clone formation rates of HepG2 transfected by PKC-alpha asODN from 0.05 micromol to 1.00 micromol were lower significantly than those of the control groups (P<0.01), and there was a dose-dependent relationship among them. The apoptosis rates of HepG2 treated with PKC-alpha asODN from 0.50 micromol to 1.00 micromol were significantly higher than those of the control groups. CONCLUSION: PKC-alpha asODN could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC.