Incidence and risk factors of breast cancer-related lymphedema in Korea: A nationwide retrospective cohort study.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a secondary lymphedema that occurs after breast cancer related treatments. BCRL develops from damage or dysfunction of the normally functioning lymphatic system due to surgery, radiation therapy and rarely due to cancer recurrence. This nationwide, retrospective study was aimed at investigating the incidence and risk factors of BCRL using the database of the Korean National Health Insurance Service (NHIS). METHODS: Patients with newly diagnosed breast cancer who underwent breast surgery from January 1, 2017 to December 31, 2020, were recruited. The incidence was compared by four groups according to the operation type of breast cancer (breast conserving surgery (BCS) with sentinel lymph node biopsy (S), BCS with axillary lymph node dissection (A), total mastectomy (TM) with S, modified radical mastectomy(MRM)). The incidence rates of lymphedema were calculated by the number of incident events by the total follow-up period. Cox proportional hazard regression was used to calculate the risk of incidence of lymphedema based on a patients' characteristics, breast cancer treatment and comorbidities. RESULTS: The final cohort of operation subjects that satisfied the inclusion criteria was 34,676. BCRL occurred in 4,242 patients (12.2%), and the median follow-up period was 695.4 days. The BCRL was diagnosed in the BCS with S (8.0%), BCS with A (23.5%), TM with S (10.7%), MRM (28.5%) with an incidence of 40.8, 132.2, 55.8 and 171.8 per 1,000 person-years, respectively. Young age, obesity, chemotherapy, radiotherapy, residence in metropolitan areas and hyperlipidemia were identified as risk factors. CONCLUSION: In Korea, the incidence of BCRL was found to be 12.2%, with the highest risk observed among patients who underwent MRM. Therefore, surgical oncologists should meticulously assess the appropriate surgical approach and consider providing education to patients with risk factors for BCRL, aiming to ensure effective prevention strategies.

The prognosis of NX stage in patients with pT1 papillary thyroid cancer who underwent lobectomy.

Lymph node (LN) metastasis is known to impact the prognosis of patients with well-differentiated thyroid cancer. Herein, we aimed to determine the effect of NX stage on the prognosis of patients with papillary thyroid cancer who underwent thyroid lobectomy. We initially selected 1257 patients who underwent thyroid cancer surgery from 2012 to 2015. Of the 1257 patients, we included 556 in the analysis, excluding patients diagnosed with other types of thyroid cancer, those who underwent total or completion thyroidectomy, and those diagnosed with LN metastasis prior to surgery. The median follow-up time was 61.8 months (range: 12.3-108.9 months). After dividing the patients into N0, N1, and NX stage groups, we performed univariate and multivariate analyses. The 5-year recurrence-free survival (RFS) was analyzed using R version 3.2.5. The mean patient age was 45.0 ± 10.9 years. Of the 556 patients, 336 patients (60.4%) were diagnosed with N0 stage, 134 (24.1%) were N1 stage, and 86 (15.5%) were NX stage. Univariate and multivariate analyses were performed to identify prognostic factors for RFS. Considering gender, age, tumor size, surgery types, extrathyroidal extension, multifocality, and recurrence, no statistically significant differences were noted between the 3 groups. The 5-year RFS rates were 98.8%, 95.5%, and 97.6% for N0, N1, and NX groups, respectively, without significant differences between the 3 groups (P = .56). Considering the T1b stage, the 5-year RFS rates were 100%, 93.1%, and 93.7% in the N0, N1, and NX groups, respectively, with a statistically significant difference between the 3 groups (P = .018). Accordingly, the NX status cannot be deemed a prognostic factor for RFS in patients with papillary thyroid cancer who underwent thyroid lobectomy. However, the benefit of prophylactic central-LN dissection should be considered in patients with well-differentiated thyroid cancer diagnosed with T1b stage.

CDDO, a PPAR-γ ligand, inhibits TPA-induced cell migration and invasion through a PPAR-γ-independent mechanism.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) acts as a key factor in breast cancer metastasis. Notably, PPAR-γ can inhibit metalloproteinase (MMP), which is involved in cancer metastasis. Our previous study revealed that PPAR-γ was related to breast cancer metastasis. The present study aimed to investigate whether the PPAR-γ ligand 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) mediated suppression of cell invasion and reduced the expression of MMP-9 in breast cancer cells. The results indicated that CDDO reduced MMP-9 expression, cell migration and invasion of breast cancer cells by inhibiting TPA-induced phosphorylation of mitogen-activated protein kinases, and downregulating the activities of activator protein-1 and nuclear factor κB. Notably, knock-out of PPAR-γ by small interfering RNA in MCF-7 cells revealed that TPA-induced MMP-9 expression occurred through a PPAR-γ-independent pathway. These data indicated that the downregulatory effect of CDDO on MMP-9 expression was affected by a mechanism independent of PPAR-γ. In conclusion, the findings of the present study suggested that CDDO may act as a key agent in the regulation of breast cancer metastasis, suggesting CDDO as a new targeted therapy for breast cancer.

Inhibition of cell invasion and migration by targeting matrix metalloproteinase-9 expression via sirtuin 6 silencing in human breast cancer cells.

Sirtuin 6 (SIRT6) regulation is involved in carcinogenesis. However, its role in breast cancer (BC) metastasis remains unclear. We investigated the effects of SIRT6 on protein kinase C activator- and cytokine-mediated cancer cell invasion and migration in MCF-7 and MDA-MB-231 cells and the association between SIRT6 and matrix metalloproteinase-9 (MMP-9) expression. To assess MMP-9 and SIRT6 expression in patients, protein levels in BC tissues were analyzed. MCF-7 and MDA-MB-231 cell viability was analyzed using MTT assays. SIRT6 was silenced in both cell lines and protein secretion, expression, and mRNA levels were analyzed. Transcription factor DNA activity was investigated using luciferase assays. Matrigel invasion assays were used to assess the effects of SIRT6 in both cell lines. SIRT6 and MMP-9 expression in cancer tissues was significantly higher than in paired normal breast tissues. 12-O-tetradecanoylphorbol-13-acetate (TPA) or tumor necrosis factor-α (TNF-α) increased MMP-9 expression and cell invasion and migration, but SIRT6 knockdown abolished these effects. SIRT6 overexpression additively increased TPA- and TNF-α-induced MMP-9 expression. SIRT6 knockdown suppressed the mitogen-activated protein kinase (MAPK) signaling pathway and thus TPA- and TNF-α-induced MMP-9 expression. SIRT6 silencing suppressed TPA- and TNF-α-induced nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) expressions in both cell lines, and treatment with MAPK, NF-κB, and AP-1 inhibitors reduced MMP-9 expression. The anti-invasive effects of SIRT6 in BC cells might be mediated by suppression of MAPK phosphorylation and reduction in NF-κB and AP-1 DNA activities, leading to MMP-9 downregulation, suggesting that SIRT6 modulation has the potential to target BC metastasis.

Downregulation of matriptase suppresses the PAR­2/PLCγ2/PKC­mediated invasion and migration abilities of MCF­7 breast cancer cells.

Matriptases, members of the type II transmembrane serine protease family, are cell surface proteolytic enzymes that mediate tumor invasion and metastasis. Matriptase is highly expressed in breast cancer and is associated with poor patient outcome. However, the cellular mechanism by which matriptase mediates breast cancer invasion remains unknown. The present study aimed to determine the role of matriptase in the protein kinase C (PKC)­mediated metastasis of MCF­7 human breast cancer cells. Matriptase small interfering RNA­mediated knockdown significantly attenuated the 12­O­tetradecanoylphorbol­13­acetate (TPA)­induced invasiveness and migration of MCF­7 cells, and inhibited the activation of phospholipase C γ2 (PLCγ2)/PKC/MAPK signaling pathways. Matriptase­knockdown also suppressed the expression of MMP­9 and inhibited the activation of NF­κB/activator protein­1 in MCF­7 cells. Additionally, GB83 [an inhibitor of protease­activated receptor­2 (PAR­2)] inhibited PKC­mediated MMP­9 expression and metastatic ability in MCF­7 cells. Furthermore, downregulation of matriptase suppressed TPA­induced MMP­9 expression and invasiveness via PAR­2/PLCγ2/PKC/MAPK activation. These findings shed light on the mechanism underlying the role of matriptase in MCF­7 cell invasion and migration ability, and suggest that matriptase modulation could be a promising therapeutic strategy for preventing breast cancer metastasis.

Analysis of BRCA1/2 variants of unknown significance in the prospective Korean Hereditary Breast Cancer study.

Genetic testing for BRCA1 and BRCA2 is crucial in diagnosing hereditary breast and ovarian cancer syndromes and has increased with the development of multigene panel tests. However, results classified as variants of uncertain significance (VUS) present challenges to clinicians in attempting to choose an appropriate management plans. We reviewed a total of 676 breast cancer patients included in the Korean Hereditary Breast Cancer (KOHBRA) study with a VUS on BRCA mutation tests between November 2007 and April 2013. These results were compared to the ClinVar database. We calculated the incidence and odds ratios for these variants using the Korean Reference Genome Database. A total of 58 and 91 distinct VUS in BRCA1 and BRCA2 were identified in the KOHBRA study (comprising 278 and 453 patients, respectively). A total of 27 variants in the KOHBRA study were not registered in the Single Nucleotide Polymorphism database. Among BRCA1 VUSs, 20 were reclassified as benign or likely benign, four were reclassified as pathogenic or likely pathogenic, and eight remained as VUSs according to the ClinVar database. Of the BRCA2 VUSs, 25 were reclassified as benign or likely benign, two were reclassified as pathogenic or likely pathogenic, and 33 remained as VUS according to the ClinVar database. There were 12 variants with conflicting interpretations of pathogenicity for BRCA1 and 18 for BRCA2. Among them, p.Leu1780Pro showed a particularly high odds ratio. Six pathogenic variants and one conflicting variant identified using ClinVar could be reclassified as pathogenic variants in this study. Using updated ClinVar information and calculating odds ratios can be helpful when reclassifying VUSs in BRCA1/2.

Bruton's agammaglobulinemia tyrosine kinase (Btk) regulates TPA­induced breast cancer cell invasion via PLCγ2/PKCß/NF­κB/AP­1­dependent matrix metalloproteinase­9 activation.

Bruton's agammaglobulinemia tyrosine kinase (BTK) is an important cytoplasmic tyrosine kinase involved in B­lymphocyte development, differentiation, and signaling. Activated protein kinase C (PKC), in turn, induces the activation of mitogen­activated protein kinase (MAPK) signaling, which promotes cell proliferation, viability, apoptosis, and metastasis. This effect is associated with nuclear factor­κB (NF­κB) activation, suggesting an anti­metastatic effect of BTK inhibitors on MCF­7 cells that leads to the downregulation of matrix metalloproteinase (MMP)­9 expression. However, the effect of BTK on breast cancer metastasis is unknown. In this study, the anti­metastatic activity of BTK inhibitors was examined in MCF­7 cells focusing on MMP­9 expression in 12­O­tetradecanoylphorbol­13­acetate (TPA)­stimulated MCF­7 cells. The expression and activity of MMP­9 in MCF­7 cells were investigated using quantitative polymerase chain reaction analysis, western blotting, and zymography. Cell invasion and migration were investigated using the Matrigel invasion and cell migration assays. BTK inhibitors [ibrutinib (10 µM), CNX­774 (10 µM)] significantly attenuated TPA­induced cell invasion and migration in MCF­7 cells and inhibited the activation of the phospholipase Cγ2/PKCß signaling pathways. In addition, small interfering RNA specific for BTK suppressed MMP­9 expression and cell metastasis. Collectively, results of the present study indicated that BTK suppressed TPA­induced MMP­9 expression and cell invasion/migration by activating the MAPK or IκB kinase/NF­κB/activator protein­1 pathway. The results clarify the mechanism of action of BTK in cancer cell metastasis by regulating MMP­9 expression in MCF­7 cells.

Hyperglycemia during Adjuvant Chemotherapy as a Prognostic Factor in Breast Cancer Patients without Diabetes.

PURPOSE: Breast cancer treatments, including chemotherapy, administered in combination with glucocorticoids can induce hyperglycemia. This study aimed to investigate the effect of hyperglycemia during adjuvant chemotherapy on the prognosis of breast cancer patients without a known history of diabetes. METHODS: In this study, 936 patients who underwent breast cancer surgery from 2010 to 2015 were initially selected as participants. Chemotherapy-related hyperglycemia was defined as fasting plasma glucose levels ≥ 100 mg/dL or random blood glucose levels ≥ 140 mg/dL during 2 or more cycles of adjuvant chemotherapy. After dividing the patients into the euglycemia and hyperglycemia groups, univariate and multivariate analyses were performed, and survival outcomes were analyzed by propensity score matching. RESULTS: The mean age of the patients was 47.4 ± 7.7 years, and the median follow-up period was 70.1 months. Eighty-two patients (19.4%) were diagnosed as having hyperglycemia. There were significant differences between the euglycemia and hyperglycemia groups with respect to age, hypertension, body mass index, axillary surgery extents, nodal stage, and total steroid dosage. T stage, vascular invasion, and hyperglycemia were identified as prognostic factors of relapse-free survival (RFS). The 5-year RFS rates were 92.0% and 82.3% in the euglycemia and hyperglycemia groups, respectively, and there was a statistically significant difference between the 2 groups (p = 0.011). The 5-year overall survival rates were 94.6% and 92.0% in the euglycemia and hyperglycemia groups, respectively, showing no statistically significant difference between the 2 groups (p = 0.113). CONCLUSION: These data suggest that hyperglycemia during adjuvant chemotherapy is a prognostic factor for RFS in breast cancer patients without diabetes.

Relative Survival Benefit by Hormonal Receptor Status of Adding Trastuzumab to Neoadjuvant Chemotherapy in Breast Cancer Patients.

PURPOSE: Neoadjuvant chemotherapy (NAC) involving trastuzumab markedly increases pathologic complete response (pCR) rates in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Despite increasing pCR rates, long-term survival gains are controversial owing to distinctive biologic behavior mediated by the presence of hormonal receptors (HRs) that may interact with HER2 receptors. We, therefore, investigated the differences in relative survival gain provided by neoadjuvant trastuzumab-based chemotherapy on HR positive (HR+) status of patients. METHODS: We retrospectively analyzed women with stage II or III HER2+ breast cancer who underwent NAC followed by a breast cancer surgery between 2008 and 2013. The survival benefits of adding trastuzumab to NAC were analyzed by classifying patients into HR+ and HR negative (HR-) groups. RESULTS: Of 666 patients included in the study, 374 (52.1%) were HR+ and 319 (47.9%) were HR-. In the HR+ group, trastuzumab treatment led to higher pCR rates and significantly better breast cancer specific survival (BCSS) and overall survival (OS) than no trastuzumab treatment. However, among patients with HR- breast cancer, trastuzumab treatment showed no statistically significant difference between BCSS and OS following multivariate analysis. CONCLUSION: We found that the addition of trastuzumab to NAC improved relative survival benefit in HER2+/HR+ patients than in HER2+/HR- patients, even though the pCR rate increases were lower. Although pCR has been regarded as a surrogate marker for estimating long-term survival benefits after NAC, it alone may not translate into real long-term oncologic outcomes in particular cancer subtypes after trastuzumab-based NAC. Further longer-term evaluation of the objective survival benefit after NAC driven by a dual HER2 block according to HR status is warranted.

15d-PGJ2 inhibits NF-κB and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism.

Activation of peroxisome proliferator-activated receptor γ (PPARγ) serves as a key factor in the proliferation and invasion of breast cancer cells and is a potential therapeutic target for breast cancer. However, the mechanisms underlying this effect remain largely unknown. Heme oxygenase-1 (HO-1) is induced and overexpressed in various cancers and is associated with features of tumor aggressiveness. Recent studies have shown that HO-1 is a major downstream target of PPARγ. In this study, we investigated the effects of induction of HO-1 by PPARγ on TPAinduced MMP-9 expression and cell invasion using MCF-7 breast cancer cells. TPA treatment increased NF-κB /AP-1 DNA binding as well as MMP-9 expression. These effects were significantly blocked by 15d-PGJ2, a natural PPARγ ligand. 15d-PGJ2 induced HO-1 expression in a dose-dependent manner. Interestingly, HO-1 siRNA significantly attenuated the inhibition of TPA-induced MMP-9 protein expression and cell invasion by 15d-PGJ2. These results suggest that 15d-PGJ2 inhibits TPA-induced MMP- 9 expression and invasion of MCF-7 cells by means of a heme oxygenase-1-dependent mechanism. Therefore, PPARγ/HO-1 signaling- pathway inhibition may be beneficial for prevention and treatment of breast cancer. [BMB Reports 2020; 53(4): 212-217].

Risk factor for contralateral occult carcinoma in patients with unilateral papillary thyroid carcinoma.

Purpose: The extent of surgery necessary in patients with unilateral papillary thyroid carcinoma (PTC) on preoperative radiologic imaging is still in doubt. In this study, we aimed to define risk factors that could be indicators for malignant nodules in the contralateral thyroid lobe. Methods: We included 438 patients who underwent total thyroidectomy between January 2011 and December 2014 at our institution. In this study, patients were divided into two groups according to the presence of contralateral occult carcinoma identified by postoperative pathological examination. We analyzed the clinicopathologic factors including characteristics of coexistent nodules in the contralateral lobe based on preoperative radiological imaging. Results: A total of 96 patients (21.9%) had PTC in the contralateral lobe. There were no significant differences between patients with or without contralateral occult carcinoma with respect to gender, age, primary tumor size, central lymph node metastasis, extrathyroidal extension and stage. The presence of Hashimoto's thyroiditis was an independent predictive factor for contralateral occult carcinoma (P=0.01). Conclusion: A risk factor for contralateral occult carcinoma in unilateral PTC patients is Hashimoto's thyroiditis. Therefore, more caution is needed when determining optimal surgical methods for PTC patients with Hashimoto's thyroiditis.

Long-term risk of congestive heart failure in younger breast cancer survivors: A nationwide study by the SMARTSHIP group.

BACKGROUND: There is a controversy about late-onset congestive heart failure (CHF) among breast cancer survivors. This study investigated the incidence rate and risk factors of late-onset CHF more than 2 years after the breast cancer diagnosis. METHODS: A nationwide, retrospective study was conducted with the National Health Information Database. With 1:3 age- and sex-matched noncancer controls, Cox proportional hazard regression models were used to analyze the incidence and risk factors of late CHF. The cumulative incidence rate of late CHF was evaluated with a Kaplan-Meier analysis and a log-rank test. RESULTS: A total of 91,227 cases (286,480 person-years) and 273,681 controls (884,349 person-years) were evaluated between January 2007 and December 2013. The risks of late CHF were higher in cases than controls (hazard ratio [HR], 1.396; 95% confidence interval [CI], 1.268-1.538). Younger survivors (age ≤ 50 years) showed a higher risk of late CHF than their younger counterparts (HR, 2.903; 95% CI, 2.425-3.474). Although older age was a risk factor for late CHF, older survivors (age ≥ 66 years) showed no difference in the risk of late CHF in comparison with their counterparts (HR, 0.906; 95% CI, 0.757-1.084). Anthracyclines and taxanes were risk factors for late CHF, although trastuzumab, radiation, and endocrine therapy were not. CONCLUSIONS: Young breast cancer survivors have a greater risk of late CHF than the young population without cancer. More attention should be paid to young breast cancer survivors who receive taxane- or anthracycline-based regimens over the long term.

Adding Ovarian Suppression to Tamoxifen for Premenopausal Breast Cancer: A Randomized Phase III Trial.

PURPOSE: The addition of ovarian function suppression (OFS) for 5 years to tamoxifen (TAM) for treatment of premenopausal patients with breast cancer after completion of chemotherapy has beneficial effects on disease-free survival (DFS). This study evaluated the efficacy of adding 2 years of OFS to TAM in patients with hormone receptor-positive breast cancer who remain in a premenopausal state or resume ovarian function after chemotherapy. PATIENTS AND METHODS: We enrolled 1,483 premenopausal women (age ≤ 45 years) with estrogen receptor-positive breast cancer treated with definitive surgery after completing adjuvant or neoadjuvant chemotherapy. Ovarian function was assessed every 6 months for 2 years since enrollment on the basis of follicular-stimulating hormone levels and vaginal bleeding history. If ovarian function was confirmed to be premenopausal at each visit, the patient was randomly assigned to complete 5 years of TAM alone (TAM-only) group or 5 years of TAM with OFS for 2 years that involved monthly goserelin administration (TAM + OFS) group. DFS was defined from the time of enrollment to the time of the first event. RESULTS: A total of 1,293 patients were randomly assigned, and 1,282 patients were eligible for analysis. The estimated 5-year DFS rate was 91.1% in the TAM + OFS group and 87.5% in the TAM-only group (hazard ratio, 0.69; 95% CI, 0.48 to 0.97; P = .033). The estimated 5-year overall survival rate was 99.4% in the TAM + OFS group and 97.8% in the TAM-only group (hazard ratio, 0.31; 95% CI, 0.10 to 0.94; P = .029). CONCLUSION: The addition of 2 years of OFS to TAM significantly improved DFS compared with TAM alone in patients who remained premenopausal or resumed ovarian function after chemotherapy.

Wet-Chemical Tuning of Li3-x PS4 (0≤x≤0.3) Enabled by Dual Solvents for All-Solid-State Lithium-Ion Batteries.

All-solid-state lithium-ion batteries (ASLBs) employing sulfide solid electrolytes are attractive next-generation rechargeable batteries that could offer improved safety and energy density. Recently, wet syntheses or processes for sulfide solid electrolyte materials have opened opportunities to explore new materials and practical fabrication methods for ASLBs. A new wet-chemical route for the synthesis of Li-deficient Li3-x PS4 (0≤x≤0.3) has been developed, which is enabled by dual solvents. Owing to its miscibility with tetrahydrofuran and ability to dissolve elemental sulfur, o-xylene as a cosolvent facilitates the wet-chemical synthesis of Li3-x PS4 . Li3-x PS4 (0≤x≤0.15) derived by using dual solvents shows Li+ conductivity of approximately 0.2 mS cm-1 at 30 °C, in contrast to 0.034 mS cm-1 for a sample obtained by using a conventional single solvent (tetrahydrofuran, x=0.15). The evolution of the structure for Li3-x PS4 is also investigated by complementary analysis using X-ray diffraction, Raman, and X-ray photoelectron spectroscopy measurements. LiCoO2 /Li-In ASLBs employing Li2.85 PS4 obtained by using dual solvents exhibit a reversible capacity of 130 mA h g-1 with good cycle retention at 30 °C, outperforming cells with Li2.85 PS4 obtained by using a conventional single solvent.

Differences in prognosis and efficacy of chemotherapy by p53 expression in triple-negative breast cancer.

PURPOSE: TP53 mutation is the most common mutation in breast cancer, and it is considered a target marker of triple-negative breast cancer (TNBC). We investigated whether expression of p53 detected by immunochemical staining predicts the chemotherapy response of TNBC. METHODS: A total of 11,393 TNBC patients who had between stage I and stage III enrolled in the Korean Breast Cancer Society Registry database from January 1, 2000 to December 31, 2015. There were 6,331 'p53-positive (+) TNBC' patients and 5062 'p53-negative (-) TNBC' patients. RESULTS: In univariate analysis, p53(+) TNBC had a worse prognosis than p53(-) TNBC in patients not receiving chemotherapy (P = 0.003). However, there was no difference in prognosis between p53(+) TNBC and p53(-) TNBC for patients receiving chemotherapy. In multivariate analysis adjusted for age and stage, the risk of p53(+) TNBC was 1.84 times higher than that of p53(-) TNBC in the non-chemotherapy group. However, there was no difference between p53(+) TNBC and p53(-) TNBC in patients receiving chemotherapy. In p53(+) TNBC, the risk was 0.6-fold lower when chemotherapy was administered than when chemotherapy was not administered. However, in p53(-) TNBC, there was no risk reduction effect by chemotherapy. CONCLUSION: The prognosis of p53(+) TNBC has worse than p53(-) TNBC, but the risk for survival was significantly reduced with chemotherapy. It suggests that p53(+) TNBC would be more sensitive to chemotherapy than p53(-) TNBC.

Assessment of Quality of Life and Safety in Postmenopausal Breast Cancer Patients Receiving Letrozole as an Early Adjuvant Treatment.

PURPOSE: There are few reports from Asian countries about the long-term results of aromatase inhibitor adjuvant treatment for breast cancer. This observational study aimed to evaluate the long-term effects of letrozole in postmenopausal Korean women with operable breast cancer. METHODS: Self-reported quality of life (QoL) scores were serially assessed for 3 years during adjuvant letrozole treatment using the Korean version of the Functional Assessment of Cancer Therapy-Breast questionnaires (version 3). Changes in bone mineral density (BMD) and serum cholesterol levels were also examined. RESULTS: All 897 patients received the documented informed consent form and completed a baseline questionnaire before treatment. Adjuvant chemotherapy was administered to 684 (76.3%) subjects, and 410 (45.7%) and 396 (44.1%) patients had stage I and II breast cancer, respectively. Each patient completed questionnaires at 3, 6, 12, 18, 24, 30, and 36 months after enrollment. Of 897 patients, 749 (83.5%) completed the study. The dropout rate was 16.5%. The serial trial outcome index, the sum of the physical and functional well-being subscales, increased gradually and significantly from baseline during letrozole treatment (p<0.001). The mean serum cholesterol level increased significantly from 199 to 205 after 36 months (p=0.042). The mean BMD significantly decreased from -0.39 at baseline to -0.87 after 36 months (p<0.001). CONCLUSION: QoL gradually improved during letrozole treatment. BMD and serum cholesterol level changes were similar to those in Western countries, indicating that adjuvant letrozole treatment is well tolerated in Korean women, with minimal ethnic variation.

Troglitazone Inhibits Matrix Metalloproteinase-9 Expression and Invasion of Breast Cancer Cell through a Peroxisome Proliferator-Activated Receptor γ-Dependent Mechanism.

PURPOSE: Peroxisome proliferator-activated receptor γ (PPARγ) is involved in the pathology of numerous diseases including atherosclerosis, diabetes, obesity, and cancer. Matrix metalloproteinases (MMPs) play a significant role in tissue remodeling related to various processes such as morphogenesis, angiogenesis, tissue repair, invasion, and metastasis. We investigated the effects of PPARγ on MMP expression and invasion in breast cancer cells. METHODS: MCF-7 cells were cultured and then cell viability was monitored in an MTT assay. Western blotting, gelatin zymography, real-time polymerase chain reaction, and luciferase assays were performed to investigate the effect of the synthetic PPARγ ligand troglitazone on MMP expression. Transcription factor DNA binding was analyzed by electrophoretic mobility shift assay. A Matrigel invasion assay was used to assess the effects of troglitazone on MCF-7 cells. RESULTS: Troglitazone did not affect MCF-7 cell viability. 12-O-tetradecanoylphorbol-13-acetate (TPA) induced MMP-9 expression and invasion in MCF-7 cell. However, these effects were decreased by troglitazone. TPA increased nuclear factor κB and activator protein-1 DNA binding, while troglitazone inhibited these effects. The selective PPARγ antagonist GW9662 reversed MMP-9 inhibition by troglitazone in TPA-treated MCF-7 cells. CONCLUSION: Troglitazone inhibited nuclear factor κB and activator protein-1-mediated MMP-9 expression and invasion of MCF-7 cells through a PPARγ-dependent mechanism.

Silencing of casein kinase 2 inhibits PKC­induced cell invasion by targeting MMP­9 in MCF­7 cells.

Casein kinase 2 (CK2) is a serine/threonine protein kinase that has been considered to represent an important factor in mammary tumorigenesis. Increased expression of matrix metalloproteinase­9 (MMP­9) via nuclear factor­κB (NF­κB) activation has been demonstrated to promote breast cancer cell invasion. In the present study, the involvement of CK2 in protein kinase C (PKC) induced cell invasion in MCF­7 breast cancer cells was investigated as well as the underlying molecular mechanisms. The mRNA and protein levels of MMP­9 in MCF­7 cells were investigated using reverse transcription­quantitative polymerase chain reaction, western blot analyses and a zymography assay. Cell invasiveness was investigated using a Matrigel invasion assay, and it was revealed that small interfering RNA specific for CK2 suppressed PKC induced cell invasion by regulating MMP­9 expression via activation of the p38 kinase/c­Jun N­terminal kinase/NF­κB pathway. In addition, it was demonstrated that CK2 inhibitors [apigenin (20 µM), emodin (20 µM) or 2­dimethylamino­4,5,6,7­tetrabromo­1H­benzimidazole (2 µM)] suppressed PKC induced cell invasion and MMP­9 expression. The results of the present study suggested that CK2 is an important factor involved in the induction of MCF­7 breast cancer cell invasion by PKC. Therefore, CK2 may represent novel candidates for therapy intended to inhibit invasion in breast cancer.

Tamoxifen therapy improves overall survival in luminal A subtype of ductal carcinoma in situ: a study based on nationwide Korean Breast Cancer Registry database.

PURPOSE: To determine the prognostic role of tamoxifen therapy for patients with ductal carcinoma in situ (DCIS) according to molecular subtypes. METHODS: Data of 14,944 patients with DCIS were analyzed. Molecular subtypes were classified into four categories based on expression of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Kaplan-Meier estimator was used for overall survival analysis while Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: Luminal A subtype (ER/PR+, HER2-) showed higher (P = .009) survival rate than triple-negative (TN) subtype. Tamoxifen therapy group showed superior (P < .001) survival than no-tamoxifen therapy group. It had survival benefit only for luminal A subtype (P = .001). Tamoxifen therapy resulted in higher survival rate in subgroups with positive ER (P = .006), positive PR (P = .009), and negative HER2 (P < .001). In luminal A subtype, tamoxifen therapy showed lower hazard ratio (HR) compared to no-tamoxifen therapy (HR, 0.420; 95% CI 0.250-0.705; P = .001). Tamoxifen therapy was a significant independent factor by multivariate analysis (HR, 0.538; 95% CI 0.306-0.946; P = .031) as well as univariate analysis. CONCLUSION: Tamoxifen therapy group showed superior prognosis than the no-tamoxifen therapy group. Its prognostic influence was only effective for luminal A subtype. Patients with luminal A subtype showed higher survival rate than those with TN subtype. Active tamoxifen therapy is recommended for DCIS patients with luminal A subtype, and routine tests for ER, PR, and HER2 should be considered for DCIS.