Background:The cancer stem cell (CSC) hypothesis has important clinical implications for cancer therapeutics because of the proposed role of CSCs in chemoresistance. The aim of this study was to investigate changes in the CSC populations before and after primary systemic therapy (PST) and their prognostic role in human breast cancer.Methods:Paired samples (before and after PST) of breast cancer tissue were obtained from clinical stage II or III patients (n=92) undergoing PST with the regimen of doxorubicin plus docetaxel (AD) (n=50) or doxorubicin plus cyclophosphamide (AC) (n=42) and subsequent breast resection. The proportions of putative CSCs with CD44+/CD24− or aldehyde dehydrogenase 1+ (ALDH1+) phenotypes were determined by immunohistochemistry.Results:A higher proportion of CD44+/CD24− tumour cells and ALDH1 positivity in pre-chemotherapy tissue was correlated with higher histologic grade, oestrogen receptor (ER) negativity, high Ki-67 proliferation index and basal-like subtype of breast cancer. Aldehyde dehydrogenase 1 positivity in pre-chemotherapy biopsy was also associated with a higher rate of pathologic complete response following PST. In comparisons of putative CSC populations before and after PST, the proportions of CD44+/CD24− and ALDH1+ tumour cells were significantly increased after PST. The cases with increased CD44+/CD24− tumour cell populations after PST showed high Ki-67 proliferation index in post-chemotherapy specimens and those with increased ALDH1+ tumour cell population after PST were associated with ER negativity and p53 overexpression. Furthermore, cases showing such an increase had significantly shorter disease-free survival time than those with no change or a reduced number of CSCs, and the survival difference was most notable with regard to the changes of ALDH1+ tumour cell population in the patients who received AC regimen.Conclusion:The present study provides the clinical evidence that the putative CSCs in breast cancer are chemoresistant and are associated with tumour progression, emphasising the need for targeting of CSCs in the breast cancer therapeutics.

A significant number of patients with breast cancer have used CAM, and health care providers should be aware of the variety of CAM methods and their patients' CAM uses for the proper management of breast cancer.

Matrix metalloproteinase-9 (MMP-9) plays an important role in the invasion and metastasis of cancer cells. In this study, we examined the inhibitory effect of bee venom (BV) and its major peptides, melittin and apamin, on PMA-induced invasion induced by MMP-9 expression in Caki-1 renal cancer cells. BV and melittin, but not apamin, significantly suppressed PMA-induced invasion by inhibiting MMP-9 expression in Caki-1 cells. Furthermore, as evidenced by MMP-9 promoter assays, melittin inhibited MMP-9 gene expression by blocking the PMA-stimulated activations of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappaB). In addition, melittin suppressed the PMA-induced phosphorylations of ERK and JNK mitogen-activated protein kinases, upstream factors involved in Ap-1 and NF-kappaB. These results suggest that the suppression of MMP-9 expression contributes to the anti-tumor properties of melittin.

ObjectiveMelittin (MEL), a major component of bee venom, has been associated with various diseases including arthritis, rheumatism and various cancers. In this study, the anti-angiogenic effects of MEL in CaSki cells that were responsive to the epidermal growth factor (EGF) were examined.Methodology/Principal FindingsMEL decreased the EGF-induced hypoxia-inducible factor-1α (HIF-1α) protein and significantly regulated angiogenesis and tumor progression. We found that inhibition of the HIF-1α protein level is due to the shortened half-life by MEL. Mechanistically, MEL specifically inhibited the EGF-induced HIF-1α expression by suppressing the phosphorylation of ERK, mTOR and p70S6K. It also blocked the EGF-induced DNA binding activity of HIF-1α and the secretion of the vascular endothelial growth factor (VEGF). Furthermore, the chromatin immunoprecipitation (ChIP) assay revealed that MEL reduced the binding of HIF-1α to the VEGF promoter HRE region. The anti-angiogenesis effects of MEL were confirmed through a matrigel plus assay.ConclusionsMEL specifically suppressed EGF-induced VEGF secretion and new blood vessel formation by inhibiting HIF-1α. These results suggest that MEL may inhibit human cervical cancer progression and angiogenesis by inhibiting HIF-1α and VEGF expression.

PurposeBreast cancer is a group of diseases with different intrinsic molecular subtypes. However, anatomic staging alone is insufficient to determine prognosis. The present study analyzed the prognostic value of the American Joint Committee for Cancer (AJCC) 8th edition cancer staging system.MethodsThis retrospective, single-center study included breast cancer cases diagnosed from January 1999 to December 2008. We restaged patients based on the 8th edition AJCC cancer staging system and analyzed the prognostic value of the anatomic and prognostic staged groups. Follow-up data including disease-free survival (DFS), overall survival (OS), and clinic-pathological data were collected to analyze the differences between the two staging subgroups.ResultsThe study enrolled 7458 breast cancer patients with a 98.7-month median follow-up. Both the 5-year DFS and OS were significantly different between the anatomic and prognostic staged groups. The 5-year OS according to disease subtype was as follows: hormone receptor-positive/human epidermal growth factor receptor 2-negative [HR(+)/HER2(−)], 90.9%; HR(+)/HER2(+), 84.7%; HR(−)/HER2(+), 81.1%; and HR(−)/HER2(−), 80.9%. According to the anatomic stage, the 5-year OS of patients with stage III HR(+)/HER2(−) disease was superior to that of patients with stage II HR(−)/HER2(−) disease (88.3 vs. 86.5%). Per the prognostic stage, both the 5-year DFS and OS rates of patients with stage II HR(−)/HER2(−) disease were higher than those of patients with stage III HR(+)/HER2(−) disease (90.1 and 94.3% vs. 79.1 and 88.9%).ConclusionsThe prognostic staging system is a refined version of the anatomic staging system and encourages a more personalized approach to breast cancer treatment.

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BackgroundAlthough distress screening is crucial for cancer survivors, it is not easy for clinicians to recognize distress. Physical activity (PA) data collected by mobile devices such as smart bands and smartphone apps have the potential to be used to screen distress in breast cancer survivors.ObjectiveThe aim of this study was to assess data collection rates of smartphone apps and smart bands in terms of PA data, investigate the correlation between PA data from mobile devices and distress-related questionnaires from smartphone apps, and demonstrate factors associated with data collection with smart bands and smartphone apps in breast cancer survivors.MethodsIn this prospective observational study, patients who underwent surgery for breast cancer at Asan Medical Center, Seoul, Republic of Korea, between June 2017 and March 2018 were enrolled and asked to use both a smartphone app and smart band for 6 months. The overall compliance rates of the daily PA data collection via the smartphone walking apps and wearable smart bands were analyzed in a within-subject manner. The longitudinal daily collection rates were calculated to examine the dropout pattern. We also performed multivariate linear regression analysis to examine factors associated with compliance with daily collection. Finally, we tested the correlation between the count of daily average steps and distress level using Pearson correlation analysis.ResultsA total of 160 female patients who underwent breast cancer surgeries were enrolled. The overall compliance rates for using a smartphone app and smart bands were 88.0% (24,224/27,513) and 52.5% (14,431/27,513), respectively. The longitudinal compliance rate for smartphone apps was 77.8% at day 180, while the longitudinal compliance rate for smart bands rapidly decreased over time, reaching 17.5% at day 180. Subjects who were young, with other comorbidities, or receiving antihormonal therapy or targeted therapy showed significantly higher compliance rates to the smartphone app. However, no factor was associated with the compliance rate to the smart band. In terms of the correlation between the count of daily steps and distress level, step counts collected via smart band showed a significant correlation with distress level.ConclusionsSmartphone apps or smart bands are feasible tools to collect data on the physical activity of breast cancer survivors. PA data from mobile devices are correlated with participants’ distress data, which suggests the potential role of mobile devices in the management of distress in breast cancer survivors.Trial RegistrationClinicalTrials.gov NCT03072966; https://clinicaltrials.gov/ct2/show/NCT03072966

Delphinidin, a polyphenol that belongs to the group of anthocyanidins and is abundant in many pigmented fruits and vegetables, possesses important antioxidant, anti‑inflammatory, anti-mutagenic and anticancer properties. In the present study, we investigated the inhibitory effects of delphinidin on vascular endothelial growth factor (VEGF) expression, an important factor involved in angiogenesis and tumor progression, in A549 human lung cancer cells. Delphinidin inhibited CoCl2- and epidermal growth factor (EGF)-induced VEGF mRNA expression and VEGF protein production. Delphinidin also decreased CoCl2- and EGF-stimulated expression of hypoxia‑inducible factor (HIF)‑1α, which is a transcription factor of VEGF. Delphinidin suppressed CoCl2- and EGF-induced hypoxia‑response element (HRE) promoter activity, suggesting that the inhibitory effects of delphinidin on VEGF expression are caused by the suppression of the binding of HIF-1 to the HRE promoter. We also found that delphinidin specifically decreased the CoCl2- and EGF-induced HIF-1α protein expression by blocking the ERK and PI3K/Akt/mTOR/p70S6K signaling pathways, whereas the p38-mediated pathways were not involved. In animal models, EGF-induced new blood vessel formation was significantly inhibited by delphinidin. Therefore, our results indicate that delphinidin has a potentially new role in anti‑angiogenic action by inhibiting HIF-1α and VEGF expression.