Serum amyloid A expression in the breast cancer tissue is associated with poor prognosis

// Mu Yang 1, * , Fangfang Liu 2, * , Kayoko Higuchi 3 , Jinko Sawashita 1, 4 , Xiaoying Fu 5 , Li Zhang 6 , Lanjing Zhang 7, 8, 9, 10 , Li Fu 2 , Zhongsheng Tong 6 , Keiichi Higuchi 1, 4 1 Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan 2 Department of Breast Pathology and Research Laboratory, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China 3 Department of Pathology, Aizawa Hospital, Matsumoto, Japan 4 Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan 5 Department of Pathology, Tianjin University of Traditional Chinese Medicine, Tianjin, China 6 Department of Breast Oncology, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China 7 Department of Pathology, University Medical Center of Princeton, Plainsboro, NJ, USA 8 Cancer Institute of New Jersey, New Brunswick, NJ, USA 9 Department of Pathology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA 10 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA * These authors contributed equally to this work Correspondence to: Keiichi Higuchi, email: keiichih@shinshu-u.ac.jp Zhongsheng Tong, email: 18622221181@163.com Keywords: breast carcinoma, serum amyloid A, tumor marker, survival, macrophages Received: January 09, 2016      Accepted: February 28, 2016      Published: April 02, 2016 ABSTRACT Background: Serum amyloid A (SAA), an acute-phase protein, is expressed primarily in the liver, and recently found also expressed in cancer tissues. However, its expression and prognostic value in breast cancer have not been described. Results: SAA protein was found expressed in tumor cells in 44.2% cases and in TAM in 62.5% cases. FISH showed more frequent SAA mRNA expression in TAM than in tumor cells (76% versus 12%, p < 0.001), and a significant association between the frequencies of SAA mRNA expression in TAM and tumor cells ( r s = 0.603, p < 0.001). The immunoreactivities of SAA protein in TAM and tumor cells were both associated with lymphovascular invasion and lymph node metastasis. Moreover, SAA-positivity in TAMs was associated with larger tumor-size, higher histological-grade, negative estrogen-receptor and progesterone-receptor statuses, and HER-2 overexpression. It was also linked to worse recurrence-free survival in a multivariable regression model. Methods: Immunohistochemistry was applied on the tumor tissues from 208 breast cancer patients to evaluate the local SAA-protein expression with additional CD68 stain to identify the tumor-associated macrophage (TAM) on the serial tissue sections. Fluorescent in situ hybridization (FISH) was conducted on serial tissue sections from 25 of the 208 tumors to examine the expression and location of SAA mRNA. Conclusions: Our results suggested that the TAMs may be a pivotal and main source of SAA production in tumor microenvironment of breast cancer. SAA immunoreactivity in TAM is associated with worse recurrence-free survival, and is therefore a biomarker candidate for postoperative surveillance and perhaps a therapeutic target for breast cancer.