Role of Escin in breast cancer therapy: potential mechanism for inducing ferroptosis and synergistic antitumor activity with cisplatin.

Breast cancer (BC) has threatened women worldwide for a long time, and novel treatments are needed. Ferroptosis is a new form of regulated cell death that is a potential therapeutic target for BC. In this study, we identified Escin, a traditional Chinese medicine, as a possible supplement for existing chemotherapy strategies. Escin inhibited BC cell growth in vitro and in vivo, and ferroptosis is probable to be the main cause for Escin-induced cell death. Mechanistically, Escin significantly downregulated the protein level of GPX4, while overexpression of GPX4 could reverse the ferroptosis triggered by Escin. Further study revealed that Escin could promote G6PD ubiquitination and degradation, thus inhibiting the expression of GPX4 and contributing to the ferroptosis. Moreover, proteasome inhibitor MG132 or G6PD overexpression could partially reverse Escin-induced ferroptosis, when G6PD knockdown aggravated that. In vivo study also supported that downregulation of G6PD exacerbated tumor growth inhibition by Escin. Finally, our data showed that cell apoptosis was dramatically elevated by Escin combined with cisplatin in BC cells. Taken together, these results suggest that Escin inhibits tumor growth in vivo and in vitro via regulating the ferroptosis mediated by G6PD/GPX4 axis. Our findings provide a promising therapeutic strategy for BC.

Analysis of preoperative influential factors and construction of a predictive nomogram of difficult thyroidectomy.

OBJECTIVE: To explore the preoperative influential factors of difficult thyroidectomy and establish a preoperative nomogram for predicting the difficulty of thyroidectomy. METHODS: A total of 753 patients who underwent total thyroidectomy with central lymph node dissection between January 2018 and December 2021 were retrospectively enrolled in this study and randomly divided into training and validation groups at a ratio of 8:2. In both subgroups, the patients were divided into difficult thyroidectomy and nondifficult thyroidectomy groups based on the operation time. Patient age, sex, body mass index (BMI), thyroid ultrasound, thyroid function, preoperative fine needle aspiration (FNA), postoperative complications and other data were collected. Logistic regression analysis was performed to identify the predictors of difficult thyroidectomy, and a nomogram predicting surgical difficulty was created. RESULTS: Multivariate logistic regression analysis demonstrated that male sex (OR = 2.138, 95% CI 1.055-4.336, p = 0.035), age (OR = 0.954, 95% CI 0.932-0.976, p < 0.001), BMI (OR = 1.233, 95% CI 1.106-1.375, p < 0.001), thyroid volume (OR = 1.177, 95% CI 1.104-1.254, p < 0.001) and TPO-Ab (OR = 1.001, 95% CI 1.001-1.002, p = 0.001) were independent risk factors for difficult thyroidectomy. The nomogram model incorporating the above predictors performed well in both the training and validation sets. A higher postoperative complication rate was found in the difficult thyroidectomy group than in the nondifficult thyroidectomy group. CONCLUSION: This study identified independent risk factors for difficult thyroidectomy and created a predictive nomogram for difficult thyroidectomy. This nomogram may help to objectively and individually predict surgical difficulty before surgery and provide optimal treatment.

Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple-negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways.

BACKGROUND: Clinical management of triple-negative breast cancer (TNBC) patients remain challenging because of the development of chemo-resistance. Identification of biomarkers for risk stratification of chemo-resistance and therapeutic decision-making to overcome such resistance is thus necessary. METHODS: Retrospective analysis was performed to identify potential stratification biomarkers. The levels of ceramide kinase (CERK) was determined in breast cancer patients. The roles of CERK and its downstream signaling pathways were analysed using cellular and biochemical assays. RESULTS: CERK upregulation was identified as a biomarker for chemotherapeutic response in TNBC. A > 2-fold change in CERK (from tumor)/CERK (from normal counterpart) was significantly associated with chemo-resistance (OR = 2.66, 95% CI 1.18-7.34), P = 0.04. CERK overexpression was sufficient to promote TNBC growth and migration, and confer chemo-resistance in TNBC cell lines, although this resistance could be overcome via CERK inhibition. Mechanistic studies suggest that CERK mediates intrinsic resistance and inferior response to chemotherapy in TNBC by regulating multiple oncogenic pathways such as Ras/ERK, PI3K/Akt/mTOR, and RhoA. CONCLUSIONS: Our work provides an explanation for the heterogeneity of chemo-response across TNBC patients and demonstrates that CERK inhibition offers a therapeutic strategy to overcome treatment resistance.

USP30 promotes the progression of breast cancer by stabilising Snail.

Breast cancer (BC) is the most prevalent tumour in women worldwide. USP30 is a deubiquitinase that has been previously reported to promote tumour progression and lipid synthesis in hepatocellular carcinoma. However, the role of USP30 in breast cancer remains unclear. Therefore, we investigated its biological action and corresponding mechanisms in vitro and in vivo. In our study, we found that USP30 was highly expressed in breast cancer samples and correlated with a poor patient prognosis. Knockdown of USP30 significantly suppressed the proliferation, invasion and migration abilities of BC cells in vitro and tumour growth in vivo, whereas overexpression of USP30 exhibited the opposite effect. Mechanistically, we verified that USP30 interacts with and stabilises Snail to promote its protein expression through deubiquitination by K48-linked polyubiquitin chains and then accelerates the EMT program. More importantly, USP30 reduced the chemosensitivity of BC cells to paclitaxel (PTX). Collectively, these data demonstrate that USP30 promotes the BC cell EMT program by stabilising Snail and attenuating chemosensitivity to PTX and may be a potential therapeutic target in BC.

Mitochondrial Uncoupling Protein-2 Ameliorates Ischemic Stroke by Inhibiting Ferroptosis-Induced Brain Injury and Neuroinflammation.

Ischemic stroke is a devastating disease in which mitochondrial damage or dysfunction substantially contributes to brain injury. Mitochondrial uncoupling protein-2 (UCP2) is a member of the UCP family, which regulates production of mitochondrial superoxide anion. UCP2 is reported to be neuroprotective for ischemic stroke-induced brain injury. However, the molecular mechanisms of UCP2 in ischemic stroke remain incompletely understood. In this study, we investigated whether and how UCP2 modulates neuroinflammation and regulates neuronal ferroptosis following ischemic stroke in vitro and in vivo. Wild-type (WT) and UCP2 knockout (Ucp2-/-) mice were subjected to middle cerebral artery occlusion (MCAO). BV2 cells (mouse microglial cell line) and HT-22 cells (mouse hippocampal neuronal cell line) were transfected with small interfering (si)-RNA or overexpression plasmids to knockdown or overexpress UCP2 levels. Cells were then exposed to oxygen-glucose deprivation and reoxygenation (OGD/RX) to simulate hypoxic injury in vitro. We found that UCP2 expression was markedly reduced in a time-dependent manner in both in vitro and in vivo ischemic stroke models. In addition, UCP2 was mainly expressed in neurons. UCP2 deficiency significantly enlarged infarct volumes, aggravated neurological deficit scores, and exacerbated cerebral edema in mice after MCAO. In vitro knockdown of Ucp2 and in vivo genetic depletion of Ucp2 (Ucp2-/- mice) increased neuronal ferroptosis-related indicators, including Fe2+, malondialdehyde, glutathione, and lipid peroxidation. Overexpression of UCP2 in neuronal cells resulted in reduced ferroptosis. Moreover, knockdown of UCP2 exacerbated neuroinflammation in BV2 microglia and mouse ischemic stroke models, suggesting that endogenous UCP2 inhibits neuroinflammation following ischemic stroke. Upregulation of UCP2 expression in microglia appeared to decrease the release of pro-inflammatory factors and increase the levels of anti-inflammatory factors. Further investigation showed that UCP2 deletion inhibited expression of AMPKα/NRF1 pathway-related proteins, including p-AMPKα, t-AMPKα, NRF1, and TFAM. Thus, UCP2 protects the brain from ischemia-induced ferroptosis by activating AMPKα/NRF1 signaling. Activation of UCP2 represents an attractive strategy for the prevention and treatment of ischemic stroke.

Matrine alleviates oxidative stress and ferroptosis in severe acute pancreatitis-induced acute lung injury by activating the UCP2/SIRT3/PGC1α pathway.

Acute lung injury (ALI) is one of the most serious complications of severe acute pancreatitis (SAP). Matrine is well known for its powerful antioxidant and antiapoptotic properties, although its specific mechanism of action in SAP-ALI is unknown. In this study, we examined the effects of matrine on SAP-associated ALIand the specific signaling pathways implicated in SAP-induced ALI, such as oxidative stress, the UCP2-SIRT3-PGC1α pathway, and ferroptosis. The administration of caerulein and lipopolysaccharide (LPS) to UCP2-knockout (UCP2-/-) and wild-type (WT) mice that were pretreated with matrine resulted in pancreatic and lung injury. Changes in reactive oxygen species (ROS) levels, inflammation, and ferroptosis in BEAS-2B and MLE-12 cells were measured following knockdown or overexpression and LPS treatment. Matrine inhibited excessive ferroptosis and ROS production by activating the UCP2/SIRT3/PGC1α pathway while reducing histological damage, edema, myeloperoxidase activity and proinflammatory cytokine expression in the lung. UCP2 knockout decreased the anti-inflammatory properties of matrine and reduced the therapeutic effects of matrine on ROS accumulation and ferroptosis hyperactivation. LPS-induced ROS production and ferroptosis activation in BEAS-2B cells and MLE-12 cells were further enhanced by knockdown of UCP2, but this effect was rescued by UCP2 overexpression. This study demonstrated that matrine reduced inflammation, oxidative stress, and excessive ferroptosis in lung tissue during SAP by activating the UCP2/SIRT3/PGC1α pathway, demonstrating its therapeutic potential in SAP-ALI.

Insight into the Crosstalk between Photodynamic Therapy and Immunotherapy in Breast Cancer.

Breast cancer (BC) is the world's second most frequent malignancy and the leading cause of mortality among women. All in situ or invasive breast cancer derives from terminal tubulobular units; when the tumor is present only in the ducts or lobules in situ, it is called ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS). The biggest risk factors are age, mutations in breast cancer genes 1 or 2 (BRCA1 or BRCA2), and dense breast tissue. Current treatments are associated with various side effects, recurrence, and poor quality of life. The critical role of the immune system in breast cancer progression/regression should always be considered. Several immunotherapy techniques for BC have been studied, including tumor-targeted antibodies (bispecific antibodies), adoptive T cell therapy, vaccinations, and immune checkpoint inhibition with anti-PD-1 antibodies. In the last decade, significant breakthroughs have been made in breast cancer immunotherapy. This advancement was principally prompted by cancer cells' escape of immune regulation and the tumor's subsequent resistance to traditional therapy. Photodynamic therapy (PDT) has shown potential as a cancer treatment. It is less intrusive, more focused, and less damaging to normal cells and tissues. It entails the employment of a photosensitizer (PS) and a specific wavelength of light to create reactive oxygen species. Recently, an increasing number of studies have shown that PDT combined with immunotherapy improves the effect of tumor drugs and reduces tumor immune escape, improving the prognosis of breast cancer patients. Therefore, we objectively evaluate strategies for their limitations and benefits, which are critical to improving outcomes for breast cancer patients. In conclusion, we offer many avenues for further study on tailored immunotherapy, such as oxygen-enhanced PDT and nanoparticles.

Efficacy, cardiotoxicity and factors affecting pathologic complete response of neoadjuvant chemotherapy with anthracycline-containing verses anthracycline-free regimens plus dual HER2 blockade for HER2-positive early-stage breast cancer: a retrospective study.

Background: The aim of this study was to compare the efficacy, cardiotoxicity and factors affecting pathologic complete response (pCR) of neoadjuvant chemotherapy (NACT) regimen TCbHP (docetaxel/nab-paclitaxel, carboplatin, trastuzumab and pertuzumab) and AC-THP (doxorubicin, cyclophosphamide followed by docetaxel/nab-paclitaxel, trastuzumab and pertuzumab) for human epidermal growth factor receptor 2-positive (HER2+) early-stage breast cancer at a retrospective cohort. Methods: This retrospective study included the patients with HER2+ early-stage breast cancer who received NACT with the regimen TCbHP or AC-THP and then underwent surgery from 2019 to 2022. pCR rate and breast-conserving rate were calculated to evaluate the efficacy of the regimens. Left ventricular ejection fraction (LVEF) from echocardiograms and abnormal electrocardiographs (ECGs) were collected to evaluate the cardiotoxicity of the two regimens. Association between the characteristics of the breast cancer lesions by magnetic resonance imaging (MRI) and the pCR rate were also explored. Results: A total of 159 patients were enrolled, including 48 patients in the AC-THP group and 111 patients in the TCbHP group. The pCR rate of the TCbHP group 64.0% (71/111) was significantly higher than that of for the the AC-THP group 37.5% (18/48) (P=0.002). Estrogen receptor (ER) status (P=0.011, OR: 0.437, 95% CI: 0.231-0.829), progesterone receptor (PR) status (P=0.001, OR: 0.309, 95% CI: 0.157-0.608) and IHC HER2 status (P=0.003, OR: 7.167, 95% CI: 1.970-26.076) were significantly correlated with the pCR rate. LVEF decreased at 6 and 12 months after treatment in the AC-THP group (P=0.024 and 0.040), which only decreased after 6 months of treatment in the TCbHP group (P=0.048). Post-NACT MRI characteristics including mass features (P<0.001) and enhancement type (P<0.001) were significantly associated with pCR rate. Conclusions: Early-stage HER2+ breast cancer treated with the TCbHP regimen has a higher pCR rate than the AC-THP group. The TCbHP regimen appears to have lower cardiotoxicity than the AC-THP regimen in terms of LVEF. Mass features and enhancement type at post-NACT MRI significantly associated with the pCR rate of breast cancer patients.

Interleukin-22 Deficiency Reduces Angiotensin II-Induced Aortic Dissection and Abdominal Aortic Aneurysm in ApoE-/- Mice.

Background: Our previous study showed that interleukin-22 (IL-22) levels were increased in patients with aortic dissection (AD). This study evaluated the effects of IL-22 on AD/abdominal aortic aneurysm (AAA) formation in angiotensin II (Ang II)-infused ApoE-/- mice. Methods: ApoE-/- mice were treated with Ang II for 28 days, and IL-22 expression was examined. In addition, the effects of IL22 deficiency on AAA/AD formation induced by Ang II infusion in ApoE-/- mice were investigated. ApoE-/-IL-22-/- mice were transplanted with bone marrow cells isolated from ApoE-/- mice or ApoE-/-IL-22-/- mice, and AAA/AD formation was observed. Results: IL-22 expression was increased in both the aortas and serum of ApoE-/- mice after Ang II infusion and was mainly derived from aortic CD4+ T lymphocytes (CD4+ TCs). IL-22 deficiency significantly reduced the AAA/AD formation as well as the maximal aortic diameter in Ang II-infused ApoE-/- mice. Decreased elastin fragmentation and reduced fibrosis were observed in the aortas of ApoE-/-IL-22-/- mice compared with ApoE-/- mice. The deletion of IL-22 also decreased aortic M1 macrophage differentiation, alleviated M1 macrophage-induced oxidative stress, and reduced aortic smooth muscle cell loss. Furthermore, M1 macrophage-induced oxidative stress was worsened and AAA/AD formation was promoted in ApoE-/-IL-22-/- mice that received transplanted bone marrow cells from ApoE-/- mice compared with those that were transplanted with bone marrow cells isolated from ApoE-/-IL-22-/- mice. Conclusions: IL-22 deficiency inhibits AAA/AD formation by inhibiting M1 macrophage-induced oxidative stress. IL-22 potentially represents a promising new target for preventing the progression of AAA/AD.

Novel application of microdissection tungsten needle in total thyroidectomy with central neck dissection for papillary thyroid carcinoma.

Background: Energy-based devices (EBD) have been popularized in thyroidectomy worldwide. Microdissection tungsten needle (MDTN) is characterized by the ultra-sharp tip providing safe and meticulous dissection with effective hemostasis. However, little study has applied MDTN in thyroidectomy. Methods: This retrospective study compared clinical data of the patients who underwent total thyroidectomy (TT) with central neck dissection (CND) using MDTN, harmonic scalpel (HS), and conventional electrocautery (CE). We assessed outcomes related to surgical efficacy and safety. The injury degree of tissue was assessed by biochemical indicators and early-stage inflammatory factors in the drainage fluid. Histological sections of the thyroid specimens were evaluated to compare levels of thermal damage by the three EBD. Results: There was a significant decrease in the intraoperative blood loss, operation time and 24-hour drainage volume in the MDTN group compared to the CE group. The total drainage volume, duration of drainage, and average length of stay of the MDTN group were less compared to the CE group though they did not reach statistical significance. No disparity was observed between the MDTN group and HS group in these variables. Total costs were not significantly different among these groups. The incidence of recurrent laryngeal nerve (RLN) injury was the lowest using MDTN compared to the CE (P = 0.034) and HS (not significant). No statistical differences were observed among these groups regarding postoperative wound pain and infection, hypoparathyroidism, and postoperative hemorrhage. Analysis of biochemical indicators showed a lower level of hemoglobin in the MDTN and HS group than the CE group (P = 0.046 and 0.038, respectively) and less triglyceride in the HS group than the MDTN and CE group (P = 0.002 and 0.029, respectively) but no significant difference in cholesterol level in these groups. Early-stage inflammatory factors including TNF-α and IL-6 showed significantly higher concentration in the CE group than the MDTN and HS group. Histological sections of thyroid specimens revealed that MDTN caused the lowest degree of thermal damage followed by HS then CE. Conclusion: MDTN exhibited comparable surgical efficacy and safety outcomes as HS in thyroidectomy. Therefore, MDTN is a safe and viable alternative for hemostasis in thyroidectomy.

PSMD12 promotes the activation of the MEK-ERK pathway by upregulating KIF15 to promote the malignant progression of liver cancer.

The tumor recurrence and drug resistance of hepatocellular carcinoma (HCC) threatened patients a lot. The mechanism should be further explored. The information of expression status and survival were available in public databases. The Western blot and immunohistochemistry staining displayed the level of related proteins. CCK-8, colony-formation assays, transwell assay and wound healing assay were performed to illustrate the ability of tumor growth, invasion and migration. In vivo model was established to verify our cell experiments. In our study, we revealed that proteasome 26S subunit, non-ATPase 12 (PSMD12) was high expressed in HCC tissues and positive related to the survival. In vitro experiments suggested that PSMD12 knockdown attenuated tumor cell growth, invasion and migration. Moreover, PSMD12 interference blocked the activation of MEK-ERK pathway. The ERK inhibitor could alleviate the tumor-promoting effect in PSMD12-overexpression cells. In addition, kinesin family member 15 (KIF15) was also observed to be highly expressed in HCC and be harmful to the survival. The public database, the images of immunohistochemistry and the western blot illustrated that PSMD12 and KIF15 was positive correlated. KIF15 knockdown impaired tumor progression and tumor-promoting effect of PSMD12. The xenograft models supported the results of cell experiments. In conclusion, PSMD12 could activated MEK-ERK pathway via KIF15 upregulation, thereby promoting tumor progression.

High Glucose Accelerates Tumor Progression by Regulating MEDAG-Mediated Autophagy Levels in Breast Cancer.

Recent studies have shown that diabetes is a major risk factor for breast cancer (BC), but the mechanism is incompletely understood. Mesenteric estrogen-dependent adipogenesis (MEDAG) plays a significant role in both glucose uptake and BC development. However, the relationship between MEDAG and BC under high glucose (HG) conditions remains unclear. In our study, MEDAG expression was higher in BC tissue from diabetic patients than in BC tissue from nondiabetic patients. HG promoted BC progression in vitro and in vivo by upregulating MEDAG expression. Furthermore, MEDAG deficiency increased the autophagosome number and autophagic flux. Moreover, inhibition of autophagy partially reversed MEDAG knockdown (MEDAGKD)-induced suppression of tumorigenic biological behaviors and epithelial-mesenchymal transition (EMT) progression. Finally, MEDAG significantly suppressed AMPK phosphorylation. Additionally, the AMPK inhibitor Compound C markedly reduced autophagosome accumulation and antitumor effects in MEDAGKD cells. Treatment with the AMPK activator AICAR exhibited similar effects in MEDAG-overexpressing (MEDAGOE) cells. In conclusion, the MEDAG-AMPK-autophagy axis is vital to BC progression in diabetic patients. Our findings provide a novel treatment target for BC in patients with diabetes.

Ferritinophagy, a form of autophagic ferroptosis: New insights into cancer treatment.

Ferritinophagy, a form of autophagy, is also an important part of ferroptosis, a type of regulated cell death resulting from abnormal iron metabolism involving the production of reactive oxygen species. As ferroptosis, autophagy and cancer have been revealed, ferritinophagy has attracted increasing attention in cancer development. In this review, we discuss the latest research progress on ferroptosis, autophagy-associated ferroptosis led by ferritinophagy, the regulators of ferritinophagy and promising cancer treatments that target ferritinophagy. Ferritinophagy is at the intersection of ferroptosis and autophagy and plays a significant role in cancer development. The discussed studies provide new insights into the mechanisms of ferritinophagy and promising related treatments for cancer.

Galeterone sensitizes breast cancer to chemotherapy via targeting MNK/eIF4E and ß-catenin.

Aberrant activation of eIF4E signalling pathway is common in breast cancer and holds potential therapeutic options. In our work, galeterone as a chemical compound under clinical trials for the treatment of prostate cancer, was identified to be effective in targeting breast cancer cells via suppressing MNK-eIF4E and ß-catenin. In despite of varying IC50, galeterone at nanomolar concentrations significantly decreased viability, proliferation and migration of a panel of breast cancer cell lines regardless of clinical subtypes and genetic mutations, and to a higher extent than in normal breast cells. Galeterone significantly enhanced the effects of chemotherapeutic drugs in reducing proliferation and viability but not migration. The in vivo efficacy of galeterone as single drug alone and its ability in augmenting chemotherapy's efficacy were also shown in breast cancer xenograft mouse model. Mechanism analysis demonstrated that galeterone decreased MNK1/2 level and phosphorylation of eIF4E. In addition, galeterone decreased ß-catenin level via promoting GSK-3ß-mediated ß-catenin degradation, and furthermore that Akt but not CK1 was involved in ß-catenin degradation by galeterone. Rescue studies demonstrated that both MNK/eIF4E and ß-catenin were responsible for anti-breast cancer activity of galeterone. Our study provides pre-clinical evidence to initialize clinical trials for breast cancer using galeterone in combination with chemotherapy.

Protein tyrosine phosphatase 1B expression contributes to the development of breast cancer.

The protein tyrosine phosphatase 1B (PTP1B) is an important regulator of metabolism. The relationship between PTP1B and tumors is quite complex. The purpose of this study is to explore the expression pattern and role of PTP1B in breast cancer. The expression of PTP1B was detected in 67 samples of breast cancer tissue by Western blot. Cell growth assay, Transwell migration assay, and Scratch motility assay were used to examine the proliferation and migration of MCF-7 with and without PTP1B. The total levels and phosphorylated levels of signal transduction and activator of transcription 3 (STAT3) and the expression of C-C motif chemokine ligand 5 (CCL5) were also examined by Western blot. PTP1B was overexpressed in over 70% of breast cancer tissues, correlating with patients with estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-positive tumors. The data also showed that both tumor size and lymph node metastasis were significantly higher in patients with a higher level of PTP1B. The proliferation and migration of MCF-7 cells were found to be inhibited after knocking down the gene of PTP1B. Our data also showed that PTP1B could up-regulate the dephosphorylated level of STAT3, which could increase the expression of CCL5. These phenomena indicated that PTP1B may play a crucial role in the development of breast cancer.

Tunicamycin-induced ER stress regulates chemokine CCL5 expression and secretion via STAT3 followed by decreased transmigration of MCF-7 breast cancer cells.

Chemokine C-C motif ligand 5 (CCL5) is an important marker related to the progression of breast cancer and is upregulated in cancer cells. However, the mechanism of the overexpression of CCL5 in tumours has not yet been clarified. The present study aimed to investigate the role of endoplasmic reticulum (ER) stress in regulating CCL5 expression and its relationship with signal transducer and activator of transcription 3 (STAT3). Meanwhile, the effect of tunicamycin, a classical ER stress inducer, and CCL5 on the transmigration of human breast cancer MCF-7 cells was observed and analysed. Compared with the normal breast epithelial tissues, expression levels of CCL5, STAT3 and CHOP, an indicator of ER stress, were significantly upregulated in breast cancer tissues. In human breast cancer MCF-7 cells, ER stress activator tunicamycin increased the expression of CCL5, STAT3 and CHOP in a time- and concentration-dependent manner. Moreover, tunicamycin-induced CCL5 expression was positively related to upregulation of unphosphorylated STAT3 (U-STAT3) but negatively related to STAT3 phosphorylation at the Tyr705 site. Furthermore, ER stress inhibited CCL5 secretion and transmigration of MCF-7 cells. This study also showed that extracellular rhCCL5 induced transmigration of MCF-7 cells which was partially blocked by the CCR5 monoclonal antibody, while knockdown of endogenous expression of CCL5 did not affect the transmigration of the cells. In conclusion, ER stress induced endogenous expression of CCL5 via elevating U-STAT3 expression; however, ER stress inhibited CCL5 secretion, which in turn, decreased the transmigration of breast cancer MCF-7 cells.

Association between diabetes mellitus and breast cancer risk: a meta-analysis of the literature.

AIM/HYPOTHESIS: Diabetes and breast cancer are both serious life-threatening diseases across the world. Some studies shows that diabetes is associated with many kinds of tumor, but links with breast cancer remain controversial. The aim of this study was to assess the association the available evidence. SUBJECTS AND METHODS: A meta-analysis was conducted including 16 studies published between 2000 and 2010 and summary relative risks(RRs) with 95% CIs were calculated using random-effects model. RESULTS: The combined evidence supports that diabetes was associated with a statistically significant 23% increased risk of breast cancer, especially in postmenopausal women (RR=1.25 95%CI 1.20-1.29). The correlation between diabetes and breast cancer was the most obvious in Europe (RR=1.88,95%CI:1.56-2.25), followed by America (RR=1.16, 95%CI:1.12-1.20). In Asia the result was not significant (RR=1.01, 95%CI=0.84-1.21). Diabetes also increased mortality from breast cancer overall (RR=1.44, 95%CI:1.31-1.58). CONCLUSIONS/INTERPRETATION: This meta-analysis indicated that diabetes can be considered as a risk factor for breast cancer. In addition, menstruation status as well as geographical distribution can affect the relationship.

Type 2 diabetes mellitus and characteristics of breast cancer in China.

Studies have showed an association between type 2 diabetes and breast cancer in Western countries. The association should be confirmed in an Asian population which has a lower incidence of breast cancer. Our study aimed to compare the clinicopathologic characteristics of breast cancers in women with and without type 2 diabetes mellitus in China. Each group included 143 cases, similar in parity, body mass index, family history, mode of diagnosis, menarche age and hormone receptors except for progesterone receptor (PR). The diabetic patients were older, with a mean age of 58.3±10 years and the percentage of postmenopausal patients was 52%, which was higher than non-diabetic patients. Significant differences were found in tumor stage, the amounts of lymph node and with metastasis, these persisting after adjustment for age. Furthermore, a positive association with higher TNM status and PR negative rate was noticed in premenopausal but not postmenopausal diabetic patients. Our results indicate that type 2 diabetes mellitus is a negative prognostic factor for breast cancer, especially in premenopausal women.