Correlated Expression ofCD47andSIRPAin Bone Marrow and in Peripheral Blood Predicts Recurrence in Breast Cancer Patients

Abstract

Purpose: CD47 plays a variety of roles in intercellular signaling. Herein, we focused on the clinicopathologic significance of CD47 expression in human breast cancer. Our data suggest that the correlation between CD47 and signal regulatory protein α (SIRPA) expression may play a key role in the progression of breast cancer.Experimental Design: Quantitative real-time PCR was used to evaluate CD47 mRNA and SIRPA mRNA expression in bone marrow and in peripheral blood from 738 cases of breast cancer.Results: In patients with high levels of CD47 expression in the bone marrow, survival was significantly poorer compared with patients with low levels of CD47 expression [disease-free survival (DFS), P = 0.0035; overall survival (OS), P = 0.015]. Furthermore, high CD47 expression group in a multivariate analysis showed significance as an independent variable for poorer prognosis in DFS (P = 0.024). In the peripheral blood, however, high CD47 expression in patients was not an independent and significant prognostic factor for DFS and OS in a multivariate analysis. CD47 expression was strongly correlated with SIRPA expression in both the bone marrow (P < 0.0001) and peripheral blood (P < 0.0001) of breast cancer patients.Conclusions: This is one of the first studies to show that a host factor in bone marrow confers prognostic importance. CD47 is an important biomarker in breast cancer, and functions as a prognostic factor for DFS. Moreover, we suggest that the poor prognosis of breast cancer patients with high expression of CD47 is due to an active CD47/SIRPA signaling pathway in circulating cells. Clin Cancer Res; 16(18); 4625-35. ©2010 AACR.The numerous efforts in breast cancer research and care have improved early detection and treatment. However, breast cancer prevalence and mortality remain at a high level every year. The prevention and therapy of breast cancer among Japanese women is a crucial public health concern. The most recent statistics for Japan document over 55,000 cases per year (1), with a mortality surpassing 12,000 per year (2). Even after apparently successful localized treatments, there are long-term risks of recurrence and metastasis. To evaluate the postsurgical risk of recurrence of breast cancer, mammography, echogram, computer tomography, and magnetic resonance imaging are utilized for diagnostic imaging, and carcinoembryonic antigen (CEA), CA15-3, and NCC-ST439 are evaluated in peripheral blood as tumor markers. However, the long-term risk of relapse is largely due to clinically occult microrecurrences and micrometastases that are currently beyond detection by current conventional screening strategies. Therefore, it is important to exploit novel tumor markers that could predict recurrence and metastasis with greater reliability.Kaplan et al. have shown that bone marrow-derived hematopoietic progenitor cells play an important role in the accumulation of premetastatic niches and the promotion of carcinogenesis and metastasis (3). We confirmed their findings by using clinical samples in which h...

TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding

“…For example, overall survival was significantly lower for DLBCL or mantle cell lymphoma patients who had elevated CD47 expression, and higher CD47 expression on tumor cells was associated with significantly poorer event-free survival in patients with CLL (7). Similar trends have been reported in other hematologic malignancies (5,6,8) and solid tumors (11,13,16,17). In addition, there is evidence to suggest that increased CD47 expression is associated with the transition from low-risk to high-risk MDS and subsequent transformation to AML (10).…”

“…Similarly, elevated CD47 expression has been demonstrated on solid tumors, including bladder, brain, breast, colon, esophageal, gastric, kidney, leiomyosarcoma, liver, lung, melanoma, ovarian, pancreatic, and prostate tumors (11)(12)(13)(14)(15). CD47 has been found to be an adverse prognostic factor where high CD47 expression correlates with more aggressive disease and poorer clinical outcomes.…”

Immune Escape and Survival Mechanisms in Circulating Tumor Cells of Colorectal Cancer

“…CD47 binds to SIRPa (46), an inhibitory receptor on macrophages and T cells (47)(48)(49) and is notably the only gene we found to be overexpressed in otherwise mostly dormant CTC. Previous studies on patients with breast cancer indicated the presence of CD47-positive CTC in the bone marrow, which may be responsible for tumor relapse (50). Other groups have shown that constitutive CD47 upregulation is a pivotal requirement for non-Hodgkin lymphoma immunotolerance and dissemination (51,52).…”

Receptor activator of nuclear factor kappa B (RANK) expression in primary breast cancer correlates with recurrence-free survival and development of bone metastases in I-SPY1 (CALGB 150007/150012; ACRIN 6657)

“…We investigated possible correlations between genes that have been described in the literature as potential contributors to the development of metastases from cancer and RANK expression [31–36,12,37–48], using both the I-SPY1 and GSE25066 cohorts. Altogether, 44 genes that could be mapped to both datasets were identified (Supplemental Table 1).…”

“…In this study, we analyzed the gene expression of the RANK/RANKL/OPG pathway in patients enrolled in the I-SPY1 clinical trial and a pooled external neoadjuvant cohort, GSE25066 [1], and correlated this gene expression with tumor and clinical features, as well as outcomes. We also evaluated correlations between other genes that may be involved in the development of metastases and RANK [31–36,12,37–48]. …”