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The objective of this study was to investigate the clinicopathological characteristics and survival outcomes of Paget disease (PD), Paget disease concomitant infiltrating duct carcinoma (PD‐IDC), and Paget disease concomitant intraductal carcinoma (PD‐DCIS). We identified 501,631 female patients from 2000 to 2013 in the Surveillance, Epidemiology, and End Results (SEER) database. These identified patients included patients with PD (n = 469), patients with PD‐IDC (n = 1832), and patients with PD‐DCIS (n = 1130) and infiltrating ductal carcinoma (IDC) (n = 498,076). Then, we compared the clinical characteristics of these patients with those who were diagnosed with IDC during the same period. The outcomes of these subtypes of breast carcinoma were different. Based on the overall survival, the patients with PD‐IDC had the worst prognosis (5‐year survival rate = 84.1%). The PD‐DCIS had the best prognosis (5‐year survival rate = 97.5%). Besides, among patients with Paget disease, the one who was married had a better prognosis than who were not. And, according to our research, the marital status was associated with the hormone receptor status in patients with PD‐IDC. Among three subtypes of Paget disease, patients with PD‐IDC had the worst prognosis. Besides, patients who were unmarried had worse outcomes. And the marital status of patients with PD‐IDC is associated with hormone status. The observation underscores the importance of individualized treatment.

// He-Fen Sun 1, 2 , Yang Zhao 1, 2 , Shui-Ping Gao 1, 2 , Liang-Dong Li 1, 2 , Wen-Yan Fu 1, 2 , Hong-lin Jiang 3 , Meng-Ting Chen 1, 2 , Li-Peng Yang 4 and Wei Jin 1, 2 1 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center of Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200030, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200030, China 3 Division of Molecular Medicine and Genetic, Department of Internal Medicine and Life Sciences Insititute, University of Michigan, Ann Abor, Michgan 48109, USA 4 Department of pathology, School of Basic Medical Sciences, Fudan University, Shanghai, 200030, China Correspondence to: Wei Jin, email: jinwei7207@163.com Keywords: male breast cancer, race, overall survival, SEER Received: December 30, 2016 Accepted: May 15, 2017 Published: May 26, 2017 ABSTRACT To investigate the clinicopathological characteristics and survival outcomes of breast cancer in the male population, 8,607 cases of patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database, including white males ( n = 7122), black males ( n = 1111), and other males (American Indian/AK Native, Asian/Pacific Islander) ( n = 374). Black male breast cancer patients were more likely to be in stages II–IV and have more advanced tumors. The rate of lymph node (LN) involvement at diagnosis was higher in black men than in whites and others. The ER- and PR-positive rates were lower in black men than in whites and others. The distant metastasis rate was higher in blacks than in whites and others. Furthermore, the overall survival (OR) rates and breast cancer-specific survival rates were significantly poorer in blacks than in whites and others (χ 2 = 29.974, P < 0.001; χ 2 = 7.285, P = 0.026, respectively). In a multivariate analysis, the results showed that race could also be a prognostic indicator ( P < 0.001). Moreover, significant differences were also observed in OS among 1:1:1 matched white, black, and other groups ( P < 0.001). Differences in outcomes may be partially explained by differences in tumor grades, LN status, and ER and PR status between the 3 groups. This study might provide insights into a better understanding of male breast cancer.

Cancer metastasis and relapse are the primary cause of mortality for patients with breast cancer. The present study performed quantitative proteomic analysis on the differentially expressed proteins between highly metastatic breast cancer cells and parental cells. It was revealed that forkhead box P2 (FOXP2), a transcription factor in neural development, may become a potential inhibitor of breast cancer metastasis. The results demonstrated that patients with a lower level of FOXP2 expression had significantly poorer relapse-free survival (P=0.0047). The transcription of FOXP2 was also significantly downregulated in breast cancer tissue compared with normal breast tissue (P=0.0005). In addition, FOXP2 may inhibit breast cancer cell migration and invasion in vitro. It was also revealed that the underlying mechanism may include the epithelial-mesenchymal transition process driven by the tumor growth factor β/SMAD signaling pathway. In conclusion, the present study identified FOXP2 as a novel suppressor and prognostic marker of breast cancer metastasis. These results may provide further insight into breast cancer prevention and the development of novel treatments.

Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype lacking effective prognostic indicators or therapeutic targets. Mitochondrial function is dysregulated frequently in cancer cells to allow for adaptation to a harsh tumor microenvironment. Targeting mitochondrial biogenesis and bioenergetics is, therefore, an attractive therapeutic strategy. In this study, we performed quantitative proteomic analyses in human parental and metastatic breast cancer cell lines to identify mitochondrial proteins involved in TNBC metastasis. We found that single-strand DNA-binding protein 1 (SSBP1) was downregulated in highly metastatic breast cancer cells. Moreover, SSBP1 downregulation promoted TNBC cell metastasis in vitro and in vivo. Mechanistically, SSBP1 loss decreased mitochondrial DNA copy number, thereby potentiating calcineurin-mediated mitochondrial retrograde signaling that induced c-Rel/p50 nuclear localization, activated TGFβ promoter activity, and TGFβ-driven epithelial-to-mesenchymal transition. Low SSBP1 expression correlated with tumor progression and poor prognosis in patients. Collectively, our findings identified SSBP1 as a novel metastasis suppressor and elucidated the mechanisms by which dysregulated mitochondrial signaling contributes to metastatic potential, providing potential new prognostic indicators for patients with TNBC. Cancer Res; 76(4); 952–64. ©2015 AACR.

TIM50 is an essential component of TIM23 complex and involved in protein translocating into the inner mitochondrial membrane. Here, we found that TIM50 was increased in breast cancer cells by SILAC. However, its biological functions and molecular mechanisms in breast cancer are poorly understood. To gain insight into the functions of TIM50 in breast cancer, we constructed two stably transfected cell lines and examined TIM50 expression in tissue samples. Our data showed that TIM50 expression was increased in breast cancer. The stable suppression of TIM50 expression through lentivirus-mediated shRNA was shown to inhibit the abilities of cancer cell proliferation and induce apoptosis. What is more, depletion of TIM50 could decrease mitochondrial membrane potential, which may be associated with cell viability. Taken together, our findings reveal a new role for TIM50 in regulating cell proliferation and apoptosis through decreasing mitochondrial membrane potential in breast cancer cell and suggest that TIM50 might be a potential target for controlling breast cancer progression.

// Wenyan Fu 1, 2, * , Hefen Sun 1, 2, * , Yang Zhao 1, 2 , Mengting Chen 1, 2 , Lipeng Yang 3 , Shuiping Gao 1, 2 , Liangdong Li 1, 2 and Wei Jin 1, 2 1 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center of Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai 200030, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200030, China 3 Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200030, China * These authors contributed equally to this work Correspondence to: Wei Jin, email: jinwei7207@163.com Keywords: breast cancer; radiotherapy; radiation sequence with surgery; survival rate; SEER Received: August 20, 2017 Accepted: December 04, 2017 Published: May 11, 2018 ABSTRACT Background: Although neoadjuvant treatment has become the established approach for women with large primary tumors or locally advanced breast cancer for which immediate surgery is not the best approach, it may also stimulate cancer stem cell self-renewal and facilitate recurrence. We sought to determine the survival outcomes of preoperative radiotherapy (PRRT) compared with postoperative radiotherapy (PORT). Materials and Methods: The Surveillance, Epidemiology, and End Results (SEER) registry was queried for patients who were diagnosed with breast cancer and underwent cancer-directed surgery. Survival analyses were performed with Cox proportional hazard regression for both overall survival (OS) and disease-specific survival (DSS), and 1:1 propensity score (PS) matching-adjusted competing risk analyses were conducted for DSS. Results: We first identified 1,111,218 eligible patients in 18 registries from 1973 to 2013 and found that, outside of the Utah registry, sequence patterns other than PORT were rarely used. Thus, we next identified eligible patients registered in Utah ( n = 7,042) from 1988 to 2007. The treatment trends shifted abruptly in 1988. Compared with the PORT group, the PRRT group showed significantly higher risks of overall mortality (absolute difference, 22.4%; P < 0.001), breast cancer-specific mortality (absolute difference, 8.6%; P < 0.001), and cardiovascular disease-specific mortality (absolute difference, 11.5%; P = 0.021). Survival differences in treatment sequences were correlated with stage. Conclusions: Substantial shifts in treatment patterns for malignant breast cancer were identified in Utah. Compared with PORT, PRRT showed significantly worse outcomes. These results could inform future standardized options for radiation sequence with surgery and further clinical trials.

Background: Cytochrome c oxidase subunit VB (COX5B), a subunit of mammalian COX, takes roles in COX assembling and functions. Online database predicts high COX5B transcription may be associated with worse disease-free survival (DFS). However, the clinical implications of COX5B in breast cancer remain unclear. Methods: We carried out immunohistochemistry on tissue microarrays of 244 patients with invasive ductal breast carcinoma to detected COX5B expression. Results: Our results suggest that COX5B protein level might be associated with tumor size. COX5B overexpression indicated a worse DFS (p < 0.05) in breast cancer. Furthermore, high COX5B expression may act as an independent factor for worse DFS in breast cancer. Conclusions: Cumulatively, our findings suggest that COX5B might serve as an important prognostic factor for breast cancer.

COX5B, a peripheral subunit of the cytochrome c oxidase complex, has previously been reported to maintain the stability of this complex. However, its functions and mechanisms involved in breast cancer progression remain unclear. Here, by performing SILAC assays in breast cancer cell models and detecting COX5B expression in tissues, we found that COX5B expression was elevated in breast cancer. Down-regulation of COX5B in breast cancer cell lines can suppress cell proliferation and induced cell senescence which was accompanied by elevating production of IL-8 and other cytokines. Interestingly, conditioned medium from COX5B knockdown cells could promote breast cancer cell migration. Mechanistic studies reveal that COX5B silence induces an increase in production of ROS, depolarization of MMP and a decrease in ATP. What's more, silence of COX5B leads to metabolic disorders, such as increased glucose uptake and decreased lactate secretion. Collectively, our study shows that loss of COX5B induces mitochondrial dysfunction and subsequently leads to cell growth suppression and cell senescence. Cytokines such as IL-8 secreted by senescent cells may in turn alter the microenvironment which could enhance cell migration. These findings may provide a novel paradigm for the treatment which combined anti-cancer drugs with particular cytokine inhibitors such as IL-8 blockers.