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The Korean Breast Cancer Society (KBCS) has established a nationwide breast cancer database using an online registration program in 1996. The present study aimed to analyze the basic findings and trends of breast cancer in Korea in 2015 using the data provided by the Korea Central Cancer Registry and the KBCS. In 2015, a total of 22,550 patients were newly diagnosed with breast cancer, of which 3,331 were carcinoma in situ cases and 19,219 were invasive cancer cases. The incidence rate of breast cancer in Korea has steadily increased since the nationwide database was established, and the crude rate and age-standardized rate including that of carcinoma in situ , were 88.1 and 66.0 cases per 100,000 women, respectively. In terms of age, the incidence of breast cancer was the highest in the 40-49-year-old age group (7,889 patients, 35.0%). With regard to surgical procedure, breast-conserving surgery was frequently performed (62.3%). However, the rate of mastectomy has been gradually increasing since 2012, that is, from 32.3% in 2014 to 36.1% in 2015. The rate of early breast cancer has continued to increase, and that of stages III and IV breast cancer was only 9.1% at the time of diagnosis. However, the 5-year survival rate of patients with carcinoma in situ from 2011 to 2015 was 92.3%, which was 14.4% higher than that from 1993 to 1995 (77.9%). Analysis of data from the nationwide registry of breast cancer will not only help to understand the characteristics of breast cancer in individuals in Korea, but will also significantly contribute to the treatment and research of breast cancer. Therefore, a high quality database for breast cancer in Korea must be established by further initiating registration project and establishing an objective legal basis., Competing Interests: CONFLICT OF INTEREST: The authors declare that they have no competing interests.

Purpose: This study aimed to evaluate the clinicopathological characteristics of pregnancy-associated breast cancer (PABC) in comparison with non-pregnancy associated breast cancer (non-PABC)., Methods: A total of 344 eligible patients with PABC were identified in the Korean Breast Cancer Society Registry database. PABC was defined as ductal carcinoma in situ , invasive ductal carcinoma, or invasive lobular carcinoma diagnosed during pregnancy or within 1 year after the birth of a child. Patients with non-PABC were selected from the same database using a 1:2 matching method. The matching variables were operation, age, and initial stage., Results: Patients with PABC had significantly lower survival rates than patient with non-PABC (10-year survival rate: PABC, 76.4%; non-PABC, 85.1%; p =0.011). PABC patients had higher histologic grade and were more frequently hormone receptor negative than non-PABC patients. Being overweight (body mass index [BMI], ≥23 kg/m 2 ), early menarche (≤13 years), late age at first childbirth (≥30 years), and a family history of breast cancer were more common in the PABC group than in the non-PABC group. Multivariate analysis showed the following factors to be significantly associated with PABC (vs. non-PABC): early menarche (odds ratio [OR], 2.165; 95% confidence interval [CI], 1.566-2.994; p <0.001), late age at first childbirth (OR, 2.446; 95% CI, 1.722-3.473; p <0.001), and being overweight (OR, 1.389; 95% CI, 1.007-1.917; p =0.045)., Conclusion: Early menarche, late age at first childbirth, and BMI ≥23 kg/m 2 were more associated with PABC than non-PABC., Competing Interests: CONFLICT OF INTEREST: The authors declare that they have no competing interests.

Purpose: Metastatic cancers spread from the primary site of origin to other parts of the body. Matrix metalloproteinase-9 (MMP-9) is essential in metastatic cancers owing to its major role in cancer cell invasion. Crotonis fructus (CF), the mature fruits of Croton tiglium L., have been used for the treatment of gastrointestinal disturbance in Asia. In this study, the effect of the ethanol extract of CF (CFE) on MMP-9 activity and the invasion of 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 cells was examined., Methods: The cell viability was evaluated using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The expression of MMP-9 was examined by Western blotting, zymography, and real-time polymerase chain reaction. An electrophoretic mobility gel shift assay was performed to detect activator protein-1 (AP-1) DNA binding activity and cell invasiveness was measured by an in vitro Matrigel invasion assay., Results: CFE significantly suppressed MMP-9 expression and activation in a dose-dependent manner. Furthermore, CFE attenuated the TPA-induced activation of AP-1., Conclusion: The results indicated that the inhibitory effects of CFE against TPA-induced MMP-9 expression and MCF-7 cell invasion were dependent on the protein kinase C δ/p38/c-Jun N-terminal kinase/AP-1 pathway. Therefore, CFE could restrict breast cancer invasiveness owing to its ability to inhibit MMP-9 activity., Competing Interests: CONFLICT OF INTEREST: The authors declare that they have no competing interests.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is considered to have applications in cancer prevention and treatment. The beneficial effects of DHA against cancer metastasis are well established; however, the mechanisms underlying these effects in breast cancer are not clear. Cell invasion is critical for neoplastic metastasis, and involves the degradation of the extracellular matrix by matrix metalloproteinase (MMP)-9. The present study investigated the inhibitory effect of DHA on MMP-9 expression and cell invasion induced by 12- O -tetradecanoylphorbol-13-acetate (TPA) in the MCF-7 breast cancer cell line. DHA inhibited the TPA-induced activation of mitogen-activated protein kinase (MAPK) and the transcription of nuclear factor (NF)-κB, but did not inhibit the transcription of activator protein-1. DHA increased the activity of peroxisome proliferator-activated receptor (PPAR)-γ, an effect that was reversed by the application of the PPAR-γ antagonist GW9662. In addition, combined treatment with GW9662 and DHA increased NF-κB-related protein expression. These results indicate that DHA regulates MMP-9 expression and cell invasion via modulation of the MAPK signaling pathway and PPAR-γ/NF-κB activity. This suggests that DHA could be a potential therapeutic agent for the prevention of breast cancer metastasis.

Purpose: Follow-up after primary treatment for breast cancer is an important component of survivor care and various international guidelines exist for the surveillance. However, little is known about current actual practice patterns of physicians whether they adhere to or deviate from recommended guidelines. The aim of this study was to determine how physicians follow-up their patients after primary treatment for breast cancer in Korea., Methods: A questionnaire survey with 34 questions in 4 categories was e-mailed to the members of Korean Breast Cancer Society from November to December 2013. Respondents were asked how they use follow-up modalities after primary treatment of breast cancer and we compared the survey results with present guidelines., Results: Of the 129 respondents, 123 (95.3%) were breast surgeons. The most important consideration in follow-up was tumor stage. History taking, physical examinations, and mammography were conducted in similar frequency recommended by other guidelines while breast ultrasonography was performed more often. The advanced imaging studies such as CT, MRI, and bone scan, which had been recommended to be conducted only if necessary, were also examined more frequently. Regular screenings for secondary malignancy were performed in 38 respondents (29.5%). Five years later after primary treatment, almost the whole respondents (94.6%) themselves monitored their patients., Conclusion: A majority of respondents have been performed more intensive follow-up modalities in comparison with present guidelines and less frequently screenings for secondary malignancy. For optimal follow-up of breast cancer survivors, tailored delivery system should be considered.

Breast cancer is the second most frequent malignancy in Korean women, with a continuously increasing incidence. The Korean Breast Cancer Society has constructed a nationwide breast cancer database through an online registration program. The aim of the present study was to report the fundamental facts on Korean breast cancer in 2011, and to analyze the changing patterns in clinical characteristics and breast cancer management in Korea over the last 10 years. Data on newly diagnosed breast cancer patients, including the total number of cases, age, stage, and type of surgery, for the year 2011 were collected from 84 hospitals and clinics nationwide using a questionnaire survey. Additional data relating to the changing patterns of breast cancer in Korea were collected from the online breast cancer registry database and analyzed. According to nationwide survey data, a total of 16,967 patients were newly diagnosed with breast cancer in 2011. The crude incidence of female breast cancer, including invasive cancer and in situ cancer, was 67 cases per 100,000 women. Analysis of the survey and registry data gave equivalent results in terms of age distribution, stage, and type of surgery. The median age at diagnosis was 50 years, and the proportion of postmenopausal women (51.3%) was higher than that of premenopausal women (48.7%) with breast cancer. The incidence of stage 0 and stage I breast cancer increased continuously over the last 10 years (56.3% in 2011), and breast conserving surgery (65.7%) was performed more frequently than total mastectomy (33.8%). The total number of breast reconstruction surgeries increased approximately 8-fold. We conclude that the clinical characteristics of breast cancer have changed over the past 10 years in Korea, and surgical management has changed accordingly. Analysis of nationwide registry data will contribute to a better understanding of the characteristics of breast cancer in Korea.

Cell invasion is required for neoplastic metastasis. Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix, is a major component in the process of cancer cell invasion. Sulfuretin is one of the major flavonoids isolated from Rhus verniciflua. Sulfuretin has been used to reduce oxidative stress, platelet aggregation, the inflammatory response and mutagenesis. However, the effect of sulfuretin on breast cancer metastasis is unknown. In this study, we investigated the inhibitory effect of sulfuretin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMP-9 expression and cell invasion in MCF-7 cells. Sulfuretin inhibited TPA-induced transcriptional activation of nuclear factor-κB (NF-κB). We demonstrated that sulfuretin mediated the inhibition of TPA-induced MMP-9 expression and that cell invasion in MCF-7 cells involved suppression of the NF-κB pathway. Therefore, inhibiting MMP-9 expression by sulfuretin may have therapeutic potential for controlling breast cancer invasiveness.

Νuclear factor-κB (NF-κB) and activator protein-1 (AP-1) are major transcription factors that have been associated with breast cancer metastasis by inducing matrix metalloproteinase-9 (MMP-9) expression. In this study, we investigated the inhibitory effects of guggulsterone isomers (cis or trans) on 12-O-tetradecanoylpho-bol-13-acetate (TPA)-induced MMP-9 expression. Cis-guggulsterone inhibited TPA-induced MMP expression by blocking IκB kinase (IKK)/NF-κB signaling, whereas trans-guggulsterone blocked mitogen-activated protein kinase (MAPK)/AP-1 signaling. Cis-guggulsterone was more potent than trans-guggulsterone in the inhibition of TPA-induced MMP-9 expression and invasion of MCF-7 cells. Furthermore, we found that the combination of these isomers exerted an additive effect on the inhibition of MCF-7 cell invasion. These results suggest that guggulsterone isomers downregulate MMP-9 expression and tumor cell invasion through the isomer-specific suppression of IKK/NF-κB and MAPK/AP-1 activation. In addition, the suppression of MMP-9 expression correlated well with the inhibition of cell invasion.

Estrogen receptor α (ERα) mediates most of the biological effects of estrogen in mammary epithelial cells and stimulates growth signals involving phosphoinositide-3-OH kinase (PI3K)/Akt in breast cancer cells. Phosphatase and tensin homologue (PTEN) is a critical counter-regulator of PI3K signaling and is thus one of the major tumor suppressors in breast cancer. Inhibition of PI3K with an inhibitor, wortmannin, increased the level of PTEN protein in ERα-positive MCF-7 cells, while levels in ERα-negative MDA-MB 231 cells were not altered. In addition, the level of PTEN protein in MCF-7 cells was significantly lower than that in MDA-MB 231 cells, which correlated with high levels of phospho-Akt and phosphatidylinositol-3,4,5,-trisphosphate (PIP3). However, PTEN mRNA expression as measured by real-time PCR showed no differences in either cell line. Notably, the levels of casein kinase 2 (CK2) and phospho-PTEN (Ser380/Thr382/383) in MCF-7 cells were lower than those in MDA-MB 231 cells, indicating that the down-regulation of PTEN protein in MCF-7 cells is caused by low levels of CK2 expression, leading to accelerated PTEN degradation. Collectively, these results suggest that ERα induces the down-regulation of PTEN through PI3K activation in breast cancer cells.

Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix (ECM), plays an important role in breast cancer cell invasion. NF-kappaB and AP-1 are known to induce MMP-9 expression. We investigated whether cordycepin, an NF-kappaB or AP-1 inhibitor, can modulate MMP-9 expression and cell invasion in MCF-7 cells. Toxicity of cordycepin was determined by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. MMP-9 expression was determined by real-time PCR, Zymography, and Western blot analysis. AP-1 activation was assayed by electrophoretic mobility shift assay (EMSA). MAPK signaling was evaluated by Western blotting with specific p-ERK, and ERK, p-p38, p38, p-JNK, JNK antibodies. Cordycepin suppressed AP-1 activation, but not NF-kappaB activation in 12-O-tetradecanoylpho-bol-13-acetate (TPA)-treated MCF-7 cells. Cordycepin inhibits TPA-induced MMP-9 expression and cell invasion by suppressing AP-1 activation. Also, cordycepin suppressed the MAPK signaling pathway. Cordycepin is a potent inhibitor of TPA-induced MMP-9 expression and blocks strongly the ability of AP-1 activation via MAPK signaling pathway in MCF-7 cells.

TNF-alpha plays a variety of biological functions such as apoptosis, inflammation and immunity. PTEN also has various cellular function including cell growth, proliferation, migration and differentiation. Thus, possible relationships between the two molecules are suggested. TNF-alpha has been known to downregulate PTEN via NF-kappaB pathway in the human colon cell line, HT-29. However, here we show the opposite finding that TNF-alpha upregulates PTEN via activation of NF-kappaB in human leukemic cells. TNF-alpha increased PTEN expression at HL-60 cells in a time- and dose-dependent manner, but the response was abolished by disruption of NF-kappaB with p65 antisense phosphorothioate oligonucleotide or pyrrolidine dithiocarbamate. We found that TNF-alpha activated the NF-kappaB pathways, evidenced by the translocation of p65 to the nucleus in TNF-alpha-treated cells. We conclude that TNF-alpha induces upregulation of PTEN expression through NF-kappaB activation in human leukemic cells.