Human endoplasmic reticulum oxidoreductin 1-a (hERO1-a) is an oxidizing enzyme that exists in the endoplasmic reticulum and its expression is augmented under hypoxia. It regulates a redox state of various kinds of protein through reoxidation of "client" protein disulfide isomerase. Interestingly, although the expression of hERO1-a in normal tissues was comparatively limited, various types of cancer cells expressed it in large amounts. Therefore, we examined the role of ERO1-a in tumor growth using murine breast cancer line 4T1 and found that knockdown of murine ERO1-a inhibited in vivo tumor growth and decreased lung metastasis compared with wild-type 4T1. Moreover, we investigated the relationship between expression of hERO1-a and prognosis in breast cancer patients. Seventy-one patients with breast cancer who underwent surgery between 2005 and 2006 in Sapporo Medical University Hospital (Sapporo, Japan) were analyzed in this study. Significant differences were found between the hERO1-a-positive group (n = 33) and hERO1-a-negative group (n = 38) in nuclear grade (P < 0.001) and intrinsic subtype (P = 0.021) in univariate analysis. More importantly, in multivariate analysis of disease-free survival by Cox regression, expression of hERO1-a was the only independent prognosis factor (P = 0.035). Finally, in univariate survival analysis, patients positive for hERO1-a had significantly shorter disease-free survival and overall survival than those patients negative for hERO1-a. These findings indicate that the expression of hERO1-a in cancer cells is associated with poorer prognosis and thus can be a prognostic factor for patients with breast cancer. (Cancer Sci 2013;
Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, "endoxifen." There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.Experimental Design: We enrolled 279 patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P ¼ 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor-positive cells in breast cancer tissues were significantly associated with Ki-67 response (P ¼ 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P ¼ 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer.
Abstract. Biomarkers that facilitate the prediction of breast cancer prognosis can improve the quality of life in patients during the long period of illness and treatment. Particularly in recent years, with the advent of a more exhaustive analysis of genetic information and gene products, the molecular mechanisms at play during breast cancer have gradually become clearer. In the present study, a systematic review of the literature between 2009 and 2014 was conducted by searching for the keywords ʻbreast cancerʼ, ʻbiomarkersʼ, ʻdiagnosisʼ, ʻprognosisʼ and ʻdrug responseʼ to clarify the present state of knowledge regarding biomarkers. In the final analysis, 16 studies on biomarkers for the breast cancer prognosis were retrieved. From these, 7 biomarkers in 9 studies were found to be strongly reliable predictors of prognosis and a further 7 biomarkers in 7 studies were poorly reliable. The use of these prognostic biomarkers should increase the options available for treatment algorithms.
Background: Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor 2 (HER2) expression. Patients with TNBC derive no benefit from molecularly targeted treatments, such as endocrine therapy or trastuzumab, as they lack the appropriate targets for these drugs. TNBC is characterized by its biological aggressiveness and poor prognosis, and consists of two subtypes, basal and nonbasal. The purpose of our study is to differentiate the clinicopathological characteristics of the two subtypes. Methods: 367 patients with primary breast cancer were recruited from April 2004 to December 2010 at 1st Department of Surgery, Sapporo Medical University. ER, PgR, and HER2 status were evaluated in all cases. Moreover, we classified TNBC into basal, nonbasal subtypes on the basis of immunohistochemical staining of epidermal growth factor receptor (EGFR), cytokeratin (CK) 5/6. Basal type was defined as CK5/6-positive and/or EGFR-positive, and nonbasal type was defined as no expression of these two markers. Results: Breast cancer subtypes by molecular classification were Hormone receptor (HR)-positive/HER2-negative (61%), HR-positive/HER2-positive (10%), HR-negative/HER2-positive (14%), and HR-negative/HER2-negative (15%). There was no difference between the basal type and the nonbasal type in clinicopathological factors. But, the basal type was significantly associated with Ki67 labeling index (p = 0.0002), p53 expression (p = 0.047), and BRCA1 expression (p = 0.03). Further, patients with the basal type TNBC showed a shorter overall survival (p = 0.032) than did patients with the nonbasal type. Conclusion: Classification of TNBC subtypes by EGFR, CK5/6 is a very useful prognostic factor, and highlights the need for the development of an adequate new strategy for the basal type TNBC.
The aim of the present study was to evaluate whether preoperative computed tomography (CT) is a useful modality for the diagnosis of axillary lymph node metastasis. The axillary lymph node status was examined in patients with primary breast cancer who had undergone surgery. In total, 75 patients were analyzed with preoperative contrast CT images, following which the patients underwent an intraoperative sentinel lymph node biopsy to determine possible predictors of axillary lymph node metastasis. The lymph node shape was classified into three groups, which included fat-, clear-and obscure-types. Multivariate analysis revealed that clear-type lymph nodes in preoperative contrast CT imaging may be an independent predictor of lymph node metastasis (odds ratio, 15; P=0.003). Therefore, the results indicated that preoperative CT examination is useful to predict axillary lymph node metastasis.
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