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Hamada T.,Kagoshima University | Souda M.,Kagoshima University | Yoshimura T.,Kagoshima University | Sasaguri S.,Kagoshima University | And 8 more authors.
Oncotarget | Year: 2014

The PCP4/PEP19 is a calmodulin-binding anti-apoptotic peptide in neural cells but its potential role in human cancer has largely been unknown. We investigated the expression of PCP4/PEP19 in human breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 cells, and found that estrogen receptor (ER)-positive MCF-7 and ER-negative SK-BR-3 cells expressed PCP4/PEP19. In the MCF-7 cells, cell proliferation was estrogen-dependent, and PCP4/PEP19 expression was induced by estrogen. In both cell lines, PCP4/PEP19 knockdown induced apoptosis and slightly decreased Akt phosphorylation. Knockdown of calcium/calmodulin-dependent protein kinase kinase 1 (CaMKK1), resulting in decreased phospho-AktThr308, enhanced apoptosis in SK-BR-3 but not in MCF-7 cells. CaMKK2 knockdown moderately decreased phospho-AktThr308 and increased apoptosis in MCF-7 cells but not in SK-BR-3 cells. These data indicated that PCP4/PEP19 regulates apoptosis but exact mechanism is still unknown. PCP4/PEP19 can therefore potentially serve as independent oncotarget for therapy of PCP4/PEP19-positive breast cancers irrespective of ER expression. Source

Takada M.,Kyoto University | Ishiguro H.,Kyoto University | Nagai S.,Saitama Cancer Center | Ohtani S.,Hiroshima City Hospital | And 20 more authors.
Breast Cancer Research and Treatment | Year: 2014

We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87 % [95 % confidence interval (CI) 85-90]. The pathologic complete response (pCR: ypT0/is + ypN0) rate was 51 %. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36 %, P < 0.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82 %, P < 0.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage [hazard ratio (HR) 2.63, 95 % CI 1.36-5.21, P = 0.004 for cN2-3 vs. cN0], histological/nuclear grade 3 (HR 1.81, 95 % CI 1.15-2.91, P = 0.011), and non-pCR (HR 1.98, 95 % CI 1.22-3.24, P = 0.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95 % CI 1.43-4.90, P = 0.002) and clinical tumor stage (HR 2.20, 95 % CI 1.16-4.20, P = 0.017 for cT3-4 vs. cT1-2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95 % CI 1.48-6.62, P = 0.003), clinical nodal stage (HR 4.26, 95 % CI 1.53-13.14, P = 0.005 for cN2-3 vs. cN0), and young age (HR 2.40, 95 % CI 1.12-4.94, P = 0.026 for ≤40 vs. ;gt40) were negative predictors for DFS. Strict pCR (ypT0 + ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95 % CI 1.31-5.97, P = 0.006 and HR 3.86, 95 % CI 1.13-24.21, P = 0.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients. © 2014 Springer Science+Business Media New York. Source

Ohi Y.,Social Medical Corporation Hakuaikai | Umekita Y.,University of Sfax | Umekita Y.,Kagoshima University | Sagara Y.,Social Medical Corporation Hakuaikai | And 10 more authors.
British Journal of Cancer | Year: 2012

Background: The one-step nucleic acid amplification (OSNA) assay is a rapid procedure for the detection of lymph node (LN) metastases using molecular biological techniques. The aim of this study was to assess the reliability of the whole sentinel lymph node (SLN) analysis by the OSNA assay as a predictor of non-SLN metastases. Methods: Consecutive 742 patients with breast cancer were enroled in the study. The association of non-SLN or ≥4 LN metastases with clinicopathological variables was investigated using multivariate logistic analysis. Results: In total, 130 patients with a positive SLN who underwent complete axillary LN dissection were investigated. The frequency of non-SLN metastases in patients who were OSNA + and + + was 19.3% and 53.4%, respectively, and that in patients with ≥4 LN metastases who were OSNA + and + + was 7.0% and 27.4%, respectively. The cytokeratin 19 (CK19) mRNA copy number (≥5.0 × 103; OSNA+ +) in the SLN was the most significant predictors of non-SLN metastases (P=0.003). The CK19 mRNA copy number (≥1.0 × 105) in the SLN was the only independent predictor of ≥4 LN metastases (P=0.014). Conclusion: Whole SLN analysis using the OSNA assay could become a valuable method for predicting non-SLN and ≥4 LN metastases. © 2012 Cancer Research UK. Source

Nakagawa S.,Tohoku University | Miki Y.,Tohoku University | Miyashita M.,Tohoku University | Hata S.,Tohoku University | And 11 more authors.
Breast Cancer Research and Treatment | Year: 2016

Invasive ductal and lobular carcinomas (IDC and ILC) are the two most common histological types of breast cancer, and have been considered to develop from terminal duct lobular unit but their molecular, pathological, and clinical features are markedly different between them. These differences could be due to different mechanisms of carcinogenesis and tumor microenvironment, especially cancer-associated fibroblasts (CAFs) but little has been explored in this aspect. Therefore, in this study, we evaluated the status of angiogenesis, maturation of intratumoral microvessels, and proliferation of CAFs using immunohistochemistry and PCR array analysis to explore the differences of tumor microenvironment between ILC and IDC. We studied grade- and age-matched, luminal-like ILC and IDC. We immunolocalized CD34 and αSMA for an evaluation of CAFs and CD31, Vasohibin-1, a specific marker of proliferative endothelial cells and nestin, a marker of pericytes for studying the status of proliferation and maturation of intratumoral microvessel. We also performed PCR array analysis to evaluate angiogenic factors in tumor stromal components. The number of CAFs, microvessel density, and vasohibin-1/CD31 positive ratio were all significantly higher in ILC than IDC but nestin immunoreactivity in intratumoral microvessel was significantly lower in ILC. These results did indicate that proliferation of CAFs and endothelial cells was more pronounced in ILC than IDC but newly formed microvessels were less mature than those in IDC. PCR array analysis also revealed that IGF-1 expression was higher in ILC than IDC. This is the first study to demonstrate the differences of tumor microenvironment including CAFs and proliferation and maturation of intratumoral vessels between ILC and IDC. © 2015, Springer Science+Business Media New York. Source

Takagi M.,Tohoku University | Miki Y.,Tohoku University | Miyashita M.,Tohoku University | Hata S.,Tohoku University | And 10 more authors.
Breast Cancer Research and Treatment | Year: 2016

The great majority of invasive lobular carcinoma (ILC) is estrogen-dependent luminal A type carcinoma but the details of estrogen actions and its intratumoral metabolism have not been well studied compared to invasive ductal carcinoma (IDC). We first immunolocalized estrogen-related enzymes including estrogen sulfotransferase (EST), estrogen sulfatase (STS), 17β-hydroxysteroid dehydrogenase (HSD) 1/2, and aromatase. We then evaluated the tissue concentrations of estrogens in ILC and IDC and subsequently estrogen-responsive gene profiles in these tumors in order to explore the possible differences and/or similarity of intratumoral estrogen environment of these two breast cancer subtypes. The status of STS and 17βHSD1 was significantly lower in ILCs than IDCs (p = 0.022 and p < 0.0001), but that of EST and 17βHSD2 vice versa (p < 0.0001 and p = 0.0106). In ILCs, tissue concentrations of estrone and estradiol were lower than those in IDCs (p = 0.0709 and 0.069). In addition, the great majority of estrogen response genes tended to be lower in ILCs. Among those genes above, FOXP1 was significantly higher in ILCs than in IDCs (p = 0.002). FOXP1 expression was reported to be significantly higher in relapse-free IDC patients treated with tamoxifen. Therefore, tamoxifen may be considered an option of endocrine therapy for luminal A type ILC patients. This is the first study to demonstrate the detailed and comprehensive status of intratumoral production and metabolism of estrogens and the status of estrogen response genes in luminal A-like ILC with comparison to those in luminal A-like IDCs. © 2016 Springer Science+Business Media New York Source

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