DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction.

Endothelial cell senescence is involved in endothelial dysfunction and vascular diseases. However, the detailed mechanisms of endothelial senescence are not fully understood. Here, we demonstrated that deficiency of developmentally regulated GTP-binding protein 2 (DRG2) induces senescence and dysfunction of endothelial cells. DRG2 knockout (KO) mice displayed reduced cerebral blood flow in the brain and lung blood vessel density. We also determined, by Matrigel plug assay, aorta ring assay, and in vitro tubule formation of primary lung endothelial cells, that deficiency in DRG2 reduced the angiogenic capability of endothelial cells. Endothelial cells from DRG2 KO mice showed a senescence phenotype with decreased cell growth and enhanced levels of p21 and phosphorylated p53, γH2AX, senescence-associated ß-galactosidase (SA-ß-gal) activity, and senescence-associated secretory phenotype (SASP) cytokines. DRG2 deficiency in endothelial cells upregulated arginase 2 (Arg2) and generation of reactive oxygen species. Induction of SA-ß-gal activity was prevented by the antioxidant N-acetyl cysteine in endothelial cells from DRG2 KO mice. In conclusion, our results suggest that DRG2 is a key regulator of endothelial senescence, and its downregulation is probably involved in vascular dysfunction and diseases.

Survival analysis in patients with invasive lobular cancer and invasive ductal cancer according to hormone receptor expression status in the Korean population.

BACKGROUND: We compared the clinicopathological characteristics and survival outcomes of invasive lobular carcinoma (ILC) cases with those of invasive ductal carcinoma (IDC) cases in various hormone receptor expression subgroups. METHODS: We compared clinicopathological characteristics, overall survival (OS), and breast cancer-specific survival (BCSS) between patients with IDC (n = 95,486) and ILC (n = 3,023). In addition, we analyzed the effects of different hormone receptor expression subgroups on survival. RESULTS: The ILC group had more instances of advanced stage and hormonal receptor positivity than did the IDC group (p < 0.001), but the IDC group had higher histological grade and nuclear grade, as well as higher frequency of human epidermal growth factor receptor 2 and Ki67 expression than did the ILC group (p < 0.001). The OS and BCSS were not significantly different between the IDC and ILC groups. The 5-year OS of the IDC group was 88.8%, while that of the ILC group was 90.6% (p = 0.113). The 5-year BCSS of the IDC group was 94.8%, while that of the ILC group was 95.0% (p = 0.552). When analyzing each hormone receptor expression subgroup, there were no significant differences in survival between the IDC and ILC groups. However, the estrogen receptor (ER) negative/progesterone receptor (PR) negative subgroup showed differences in survival between the IDC and ILC groups. Moreover, the hazard ratio of ILC in the ER negative/PR negative subgroup was 1.345 (95% confidence interval: 1.012-1.788; p = 0.041). CONCLUSIONS: Hormone receptor expression should be considered when determining prognosis and treatment regimen for IDC and ILC. Researchers should further study the ER negative/PR negative population to identify treatment and prognostic models that will facilitate the development of individualized therapy for these patients, which is needed for good outcomes.

"Teachable Moment": Effects of an Educational Program on Knowledge and Quality of Life of Korean Breast Cancer Survivors.

Due to prolonged survival and the relatively young median age of patients, the quality of life (QOL) of breast cancer survivors is an important issue in Korea. We conducted an educational program for breast cancer survivors, and evaluated its impact on knowledge, QOL, and lifestyle changes. This study utilized a single-arm pretest-posttest design. Participants were tested before and after an educational program to measure changes in knowledge. To measure QOL change, we conducted a QOL survey at the time of enrollment and again 6 months later. Regarding the knowledge test, mean scores increased from 9.62 to 14.74 points following education (p < 0.001). After 6 months, 97 patients completed the QOL survey and the data were analyzed, showing significant improvements in anxiety (p = 0.021), depression (p = 0.003), functional well-being (p = 0.005), and breast cancer subscales of the Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) (p < 0.001). Additionally, the rates of adequate exercise significantly improved (p < 0.001), while rates of alcohol consumption and second cancer screening did not significantly change. One educational program session can improve patient knowledge, QOL, and psychosocial well-being, but is insufficient to achieve significant changes in health behavior.

Clinical Outcomes Following Letrozole Treatment according to Estrogen Receptor Expression in Postmenopausal Women: LETTER Study (KBCSG-006).

PURPOSE: In this trial, we investigated the efficacy and safety of adjuvant letrozole for hormone receptor (HR)-positive breast cancer. Here, we report the clinical outcome in postmenopausal women with HR-positive breast cancer treated with adjuvant letrozole according to estrogen receptor (ER) expression levels. METHODS: In this multi-institutional, open-label, observational study, postmenopausal patients with HR-positive breast cancer received adjuvant letrozole (2.5 mg/daily) for 5 years unless they experienced disease progression or unacceptable toxicity or withdrew their consent. The patients were stratified into the following 3 groups according to ER expression levels using a modified Allred score (AS): low, intermediate, and high (AS 3-4, 5-6, and 7-8, respectively). ER expression was centrally reviewed. The primary objective was the 5-year disease-free survival (DFS) rate. RESULTS: Between April 25, 2010, and February 5, 2014, 440 patients were enrolled. With a median follow-up of 62.0 months, the 5-year DFS rate in all patients was 94.2% (95% confidence interval [CI], 91.8-96.6). The 5-year DFS and recurrence-free survival (RFS) rates did not differ according to ER expression; the 5-year DFS rates were 94.3% and 94.1%in the low-to-intermediate and high expression groups, respectively (p = 0.6), and the corresponding 5-year RFS rates were 95.7% and 95.4%, respectively (p = 0.7). Furthermore, 25 patients discontinued letrozole because of drug toxicity. CONCLUSION: Treatment with adjuvant letrozole showed very favorable treatment outcomes and good tolerability among Korean postmenopausal women with ER-positive breast cancer, independent of ER expression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01069211.

Tristetraprolin posttranscriptionally downregulates PFKFB3 in cancer cells.

The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases 3 (PFKFB3) catalyzes the first committed rate-limiting step of glycolysis and is upregulated in cancer cells. The mechanism of PFKFB3 expression upregulation in cancer cells has not been fully elucidated. The PFKFB3 3'-UTR is reported to contain AU-rich elements (AREs) that are important for regulating PFKFB3 mRNA stability. However, the mechanisms by which PFKFB3 mRNA stability is determined by its 3'-UTR are not well known. We demonstrated that tristetraprolin (TTP), an ARE-binding protein, has a critical function regulating PFKFB3 mRNA stability. Our results showed that PFKFB3 mRNA contains three AREs in the 3'-UTR. TTP bound to the 3rd ARE and enhanced the decay of PFKFB3 mRNA. Overexpression of TTP decreased PFKFB3 expression and ATP levels but increased GSH level in cancer cells. Overexpression of PFKFB3 cDNA without the 3'-UTR rescued ATP level and GSH level in TTP-overexpressing cells. Our results suggested that TTP post-transcriptionally downregulated PFKFB3 expression and that overexpression of TTP may contribute to suppression of glycolysis and energy production of cancer cells in part by downregulating PFKFB3 expression.

Doxorubicin inhibits PD-L1 expression by enhancing TTP-mediated decay of PD-L1 mRNA in cancer cells.

Recent research revealed that doxorubicin (DOX) decreased expression of programmed death-ligand 1 (PD-L1) in cancer cells. However, the detailed mechanisms underlying this effect are not well established. Here, we demonstrate that doxorubicin down-regulates PD-L1 expression through induction of AU-rich element (ARE) binding protein tristetraprolin (TTP) in cancer cells. PD-L1 mRNA contain three AREs within its 3'UTR. Doxorubicin induced expression of TTP, increased TTP binding to the 3rd ARE of the PD-L1 3'UTR, and increased decay of PD-L1 mRNA. Inhibition of TTP abrogates the inhibitory effect of doxorubicin on PD-L1 expression. Our data suggest that TTP plays a key role in doxorubicin-mediated down-regulation of PD-L1 by enhancing degradation of PD-L1 mRNA in cancer cells.

Survival benefit of postoperative radiotherapy for ductal carcinoma in situ after breast-conserving surgery: a Korean population-based cohort study.

PURPOSE: It has been accepted that radiation therapy (RT) for ductal carcinoma in situ (DCIS) has no survival benefit despite increasing local control. However, a recent large database study reported a small but significant benefit. Using a Korean population-based large database, we examined the survival benefit of RT for DCIS after breast-conserving surgery (BCS) and analyzed which subgroup might derive benefit from it. METHODS: Data from 6038 female DCIS patients who underwent BCS with or without RT between 1993 and 2012 were included in this study. We used propensity score analysis to control for differences in baseline characteristics. RESULTS: Before adjusting, patients who received RT were more likely to have a large-sized tumor, poor histologic grade, poor nuclear grade, and less hormone receptor positivity. Ten-year overall survival (OS) rates were 95.0% in the non-RT group and 97.1% in the RT group (p < 0.001). After adjusting, previously noted differences of characteristics were substantially reduced, and then ten-year OS rates were 94.3% in the non-RT group and 97.6% in the RT group (p = 0.001). When examining the benefit of RT according to proposed prognostic scores, patients with a score of 0 showed no difference in OS by adding RT after BCS, whereas those with high scores demonstrated a significant benefit. CONCLUSIONS: We demonstrated the significant OS benefit of postoperative RT after BCS based on a large database, and for the first time beyond the western population. The omission of RT for selected patients to prevent overtreatment needs to be more elaborately studied.

Clinical implication of subcategorizing T2 category into T2a and T2b in TNM staging of breast cancer.

Regarding TNM staging in breast cancer, T2 category is currently not divided into subcategories even though it covers a wider range of tumor sizes than T1 category. Using Korean Breast Cancer Registry database, data of 41 071 women diagnosed as non-metastatic T2 breast cancer between 2001 and 2014 were analyzed. Cutoff value for optimal tumor size was approximated by receiver operating characteristic (ROC) curve to subcategorize T2 tumors. Overall survival (OS) was compared between two subcategories. Median follow-up period was 65 months. Of 41 071 patients, 4504 (11.0%) died. Based on ROC curve analysis, 3.0 cm was selected as the cutoff value. Five-year OS rate was 91% in patients with breast tumors ≤3.0 cm (T2a) and 86% in patients with breast tumors >3.0 cm (T2b) (log-rank P < 0.001). T2b subcategory showed worse OS than T2a subcategory regardless of node status (log-rank P < 0.001 for all node categories). Within every subgroup defined by primary OS analysis covariates, T2b subcategory consistently showed worse outcome compared to T2a subcategory. By multivariate analysis, T2b subcategory was a significant independent prognostic factor of OS (hazard ratio: 1.26, 95% CI = 1.18-1.34). T2 category of breast cancer could be subcategorized into T2a and T2b with a cutoff value of 3 cm. These subcategories definitely showed different OSs even after adjusted for known prognostic factors. Subcategorization of T2 category might be useful for predicting prognosis more accurately and tailoring adjuvant therapy.

Spindle epithelial tumor with thymus-like differentiation of the thyroid in a 70-year-old man.

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare tumor of the thyroid gland mostly occurring in young patients. The imaging findings of SETTLE tumors are yet to be defined. However, they are usually described as well-defined heterogeneously enhanced masses on CT scan. The current case has the potential growth as compared with a 2009 chest radiography. We took into account the possibility of SETTLE in the case of a bulky mass in patients over 70 years old, particularly in the lower neck. Herein, we report a case of the oldest patient so far. The patient underwent a right lobectomy of the thyroid and mass excision. Follow-up CT scans after 6 months revealed no local recurrence. Surgery is the gold standard treatment for SETTLE. Chemotherapy and radiotherapy could be another possible option for patients with advanced stage SETTLE.

Clinicopathologic Characteristics of Pregnancy-Associated Breast Cancer: Results of Analysis of a Nationwide Breast Cancer Registry Database.

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/m2), 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/m2 were more associated with PABC than non-PABC.

Radiation-related heart disease after breast cancer radiation therapy in Korean women.

PURPOSE: To study the late cardiac toxicity of breast radiation therapy (RT) in Asian women. METHODS: Female breast cancer patients in Korea who underwent breast conservation surgery followed by RT from 1990-2012 were identified from two large registries at institution and population levels. Cumulative incidences of acute coronary events (ACE) or cardiac mortality were estimated in relation to the laterality of breast cancer using a competing risks analysis. RESULTS: In an analysis of 2577 women from a single institution, 3.7% were obese (body mass index ≥30), and 3.4% were ever-smokers. Patients with a history of hypertension, diabetes, or coronary artery disease were 17.5, 5.7, and 2.8%, respectively. The mean heart doses were 6.2 and 1.5 Gy for left- and right-sided tumors, respectively. With a median follow-up of 7 (range 1-23) years, the overall and breast cancer-specific survivals at 10 years were 94.9 and 96.5%, respectively. The 10-year cumulative incidence of ACE was 2.96%. The mean time to ACE was 5.2 ± 3.9 years (range 1-17). There was no clinically relevant difference in rates of ACE between left-sided and right-sided patients, with an adjusted hazard ratio of 1.16 (CI 0.59-2.29). An analysis of 24,235 women in a nationwide registry validated these negative findings with respect to cardiac mortality, with an adjusted hazard ratio of 1.52 (CI 0.37-6.25). Increasing age, a higher body mass index, and a history of hypertension or ischemic heart disease were identified as risk factors. CONCLUSIONS: Our findings reassure that excess risk from breast RT may be small in healthy women, most of who not smoke, weigh less, and have fewer risk factors. A validation using a larger data set of National Health Insurance Corporation is ongoing.

Mini-breast reconstruction with an omental flap: a retrospective clinical study.

INTRODUCTION: Potential challenges associated with immediate small breast reconstruction include an inadequate size of the donor site, a thinner skin envelope and limited selection of implants. We present immediate postmastectomy reconstruction of small breasts with a laparoscopically harvested pedicled omental flap (LHPOF) in five Korean women. METHODS: From December 2014 to July 2015, we performed immediate postmastectomy reconstruction with an LHPOF in five breast cancer patients. Data on the patients' age; body mass index; tumour size; site, type and weight of the mastectomy specimen; operative time; hospital stay; complications; postoperative chemotherapy or radiation therapy; and follow-up duration were reviewed in this retrospective clinical study. RESULTS: The mean mastectomy specimen weight was 212 g (range: 104-272 g). The mean operative time was 298 min (range: 240-380 min), and the mean harvesting time was 75 min (range: 65-90 min). There were no flap-related complications such as fat necrosis or flap loss and no donor site-related complications such as bowel dysfunction, an epigastric bulge or hernia during the follow-up period (average: 8.2 months, range: 5-11 months). The cosmetic results were satisfactory. DISCUSSION: The LHPOF can be useful for immediate postmastectomy reconstruction of small breasts, because it provides a soft and naturally ptotic appearance of the reconstructed breast (versus implant-based reconstruction) with low donor-site morbidity (versus other autologous tissue reconstruction approaches).

Follow-up bone scan in breast cancer patients: what is the appropriate interpretation of purely rib uptake?

AIM: Although rib uptake is frequently detected in follow-up bone scans of breast cancer patients, few studies have assessed its clinical significance. PATIENTS AND METHODS: Among 1208 breast cancer patients who underwent a bone scan between 2011 and 2014, 157 patients presented with newly detected rib uptake at follow-up. Patients who had underlying bone metastases (n=8) or had simultaneous new uptake in sites other than the rib (n=13) were excluded. The patients enrolled finally were those who had purely rib uptakes. The location, intensity, and final diagnosis of the uptake were evaluated by nuclear medicine physicians. RESULTS: A total of 275 new instances of rib uptake were detected in follow-up bone scans of 136 patients. These were more frequently located on the ipsilateral side of the breast cancer (61.1%) and the anterior arc (65.1%), and they presented as moderate to intense (93.1%) uptakes. Among these, 265 lesions in 130 patients turned out to be benign fractures (96.4%), whereas only 10 lesions in six patients were metastases. The proportion of metastases was significantly higher if the uptake was linear or if the patient had recurrence. It was marginally higher if the uptake was located in the posterior arc. The proportion of metastases within the radiation field was significantly lower in patients with a history of irradiation. CONCLUSION: Newly detected purely rib uptake on a follow-up bone scan in patients who have been treated for breast cancer is mostly because of fractures and rarely signals metastasis. However, if the patient has disease recurrence, metastasis should strongly be suspected, particularly when uptake is linear or located in the posterior arc.

Characterization of Korean Male Breast Cancer Using an Online Nationwide Breast-Cancer Database: Matched-Pair Analysis of Patients With Female Breast Cancer.

The aim of this study is to review the characteristics and the survival rate in male breast cancer (MBC) patients in Korea over a 31-year period. Additionally, we analyzed the overall survival (OS) rate of a group of MBC matched to females with breast cancer. We retrospectively analyzed the data from 400 Korean patients who were treated for MBC from 1978 to 2009. Patient demographics and clinical information were routinely documented throughout the study period. Survival and prognostic factors were evaluated. Each MBC patient was matched with 5 female breast cancer (FBC) patients based on 7 characteristics and we compared the OS rates between the 2 groups. For MBC cases, the median follow-up was 72 months and the 5-year OS rate was 85.9%. In univariate analyses, the prognostic factors influencing OS were age (more than 60 years, P <0.001), tumor size (>2 cm, P = 0.007), and having a negative progesterone receptor (PR) status (P = 0.042). Only the age (P = 0.028) and tumor size (P = 0.024) were significant prognostic factors for OS in multivariate analysis. After matching, we had 260 male patients matched to 1300 female patients for analysis. Compared with cases among females, the rate of mastectomy was higher among MBC cases and tumors, which were almost invasive ductal carcinomas (IDCs), were more likely to be located in the central part of the breast. For MBC cases, the percentage of adjuvant radiation therapy was low compared with female cases. The primary hormone therapy agent used was tamoxifen. The 5-year OS rates were similar in MBC compared with FBC (91.0% vs. 92.6%, P = 0.300). We found that only the age (more than 60 years) and tumor size were independent prognostic factors of survival in MBC. The prognosis for MBC is similar to that for FBC given similar stage and hormone-receptor status.

TTP mediates cisplatin-induced apoptosis of head and neck cancer cells by down-regulating the expression of Bcl-2.

The chemotherapeutic agent cisplatin is widely used for treatment of head and neck squamous cell carcinoma (HNSCC). B-cell lymphoma 2 (Bcl-2) is an anti-apoptotic protein that is overexpressed in cancer cells and confers resistance to cisplatin. Thus, inhibition of Bcl-2 expression may enhance the cisplatin sensitivity of cancer cells. In this study, we report that the AU-rich element (ARE) binding protein tristetraprolin (TTP) inhibits the expression of Bcl-2 and enhances cisplatin sensitivity of HNSCC cells. Cisplatin-sensitive HNSCC cells express high levels of TTP and low levels of Bcl-2, while cisplatin-resistant HNSCC cells have low levels of TTP and high levels of Bcl-2. Inhibition of TTP expression using siRNA increases levels of Bcl-2 and decreases cisplatin sensitivity in HNSCC cells. On the contrary, overexpression of TTP decreases Bcl-2 expression and increases sensitivity to cisplatin. Together, the results of the present study suggest that TTP expression enhances cisplatin sensitivity in HNSCC cells by reducing levels of Bcl-2.

A comparison of the clinical outcomes of patients with invasive lobular carcinoma and invasive ductal carcinoma of the breast according to molecular subtype in a Korean population.

BACKGROUND: To investigate the clinicopathological characteristics and the survival outcomes of invasive lobular carcinoma (ILC) patients compared to invasive ductal carcinoma (IDC) patients according to their molecular subtype. METHODS: We compared the clinicopathological characteristics, breast cancer-specific survival (BCSS) and overall survival (OS) between patients with IDC (n = 14,547) and ILC (n = 528). RESULTS: The ILC presented with a larger tumor size, more advanced cancer stage, increased rate of hormonal receptor positivity, human epidermal growth factor 2 (HER2) negativity and mastectomy than the IDC. The ILC patients more frequently presented with the luminal A subtype, whereas the IDC patients more frequently presented with the luminal B, HER2-overexpression, or triple negative subtype. The BCSS and OS were not significantly different between the IDC and ILC for each molecular subtype. CONCLUSIONS: Similar to IDC patients, molecular subtype should be considered when determining the prognosis and treatment regimen for ILC patients.

Effect of axillary lymph node dissection after sentinel lymph node biopsy on overall survival in patients with T1 or T2 node-positive breast cancer: report from the Korean Breast Cancer Society.

BACKGROUND: The effect of axillary lymph node dissection (ALND) after sentinel lymph node biopsy (SLNB) in patients with clinically node-negative patients in preoperative evaluations on overall survival (OS) is uncertain. The study aimed to evaluate the difference of survival between node-positive patients who underwent SLNB alone and those who received ALND after SLNB using the Korean Breast Cancer Society registry. METHODS: We enrolled 2,581 patients who met the eligibility criteria. All enrolled patients had T1 or T2 breast cancer, and received mastectomy or breast-conserving treatment followed by documented adjuvant systemic therapy. RESULTS: There were 197 patients with SLNB alone and 2,384 patients with ALND after SLNB. Smaller tumor size, lower number of nodal metastasis, and higher proportion of breast-conserving surgery were found in patients with SLNB alone than in those with ALND after SLNB. There was no significant difference in OS between the two groups by the log-rank test. ALND after SLNB showed no significant improvement in OS in multivariate analysis. CONCLUSIONS: ALND in patients with sentinel metastasis who have T1 or T2 breast cancer receiving adjuvant systemic therapy may not have improved OS.

Tumor suppressor p53 plays a key role in induction of both tristetraprolin and let-7 in human cancer cells.

Tristetraprolin (TTP) and let-7 microRNA exhibit suppressive effects on cell growth through down-regulation of oncogenes. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. However, the precise mechanism of this repression is unknown. We here demonstrate that p53 stimulated by the DNA-damaging agent doxorubicin (DOX) induced the expression of TTP in cancer cells. TTP in turn increased let-7 levels through down-regulation of Lin28a. Correspondingly, cancer cells with mutations or inhibition of p53 failed to induce the expression of both TTP and let-7 on treatment with DOX. Down-regulation of TTP by small interfering RNAs attenuated the inhibitory effect of DOX on let-7 expression and cell growth. Therefore, TTP provides an important link between p53 activation induced by DNA damage and let-7 biogenesis. These novel findings provide a mechanism for the widespread decrease in TTP and let-7 and chemoresistance observed in human cancers.