Co-expression of MET and CD47 is a novel prognosticator for survival of luminal-type breast cancer patients

Abstract

Although luminal-type primary breast cancer can be efficiently treated, development of metastatic disease remains a significant clinical problem. We have previously shown that luminal-type circulating tumor cells (CTCs) co-expressing the tyrosine-kinase MET and CD47, a ligand involved in cancer cell evasion from macrophage scavenging, are able to initiate metastasis in xenografts. Here, we investigated the clinical relevance of MET-CD47 co-expression in 255 hormone receptor positive breast tumors by immunohistochemistry and found a 10.3-year mean overall-survival difference between MET-CD47 double-positive and double-negative patients (p<0.001). MET-CD47 co-expression defined a novel independent prognosticator for overall-survival by multivariate analysis (Cox proportional hazards model: HR: 4.1, p<0.002) and CD47 expression alone or in combination with MET was strongly associated with lymph node metastasis. Furthermore, flow cytometric analysis of metastatic patient blood revealed consistent presence of MET+CD47+ CTCs (range 0.8 – 33.3% of CTCs) and their frequency was associated with increased metastatic spread. Finally, primary uncultured CTCs with high MET+CD47+ content showed an enhanced capacity to initiate metastasis in mice. Detection and targeting of MET and CD47 may thus provide a rational basis for risk stratification and treatment of patients with luminal-type breast cancer.

HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

“…6C). Similar results were recently reported regarding the immunohistochemical detection of CD47 protein expression in breast cancer biopsies (48).…”

“…In three different breast cancer cell lines, which represent luminal/ER + (MCF7), HER2-enriched (HCC1954), and basal-like/triple-negative (SUM159) subtypes of breast cancer, the expression of CD47 mRNA and protein was induced by hypoxia in a HIF-dependent manner. A recent study reported that CD47 protein was detected in 5% of hormone receptor positive, HER2 − breast cancers (48). Our bioinformatic analysis suggests that CD47 expression is likely to be higher among triple-negative breast cancers, most of which fall into the basal-like molecular subtype that is characterized by increased expression of the HIF transcriptome (18,39).…”

Characterization of cluster of differentiation�47 expression and its potential as a therapeutic target in esophageal squamous cell cancer

“…The binding of CD47 to signal regulatory protein α (SIRPα), which is expressed on myeloid cells, induces an inhibitory 'do not eat me' signal that attenuates macrophage phagocytic activity (15). CD47 is highly expressed in many different types of cancer, including breast, ovarian, colon and bladder cancer, glioblastoma and various hematological types of cancer (16)(17)(18)(19)(20)(21)(22). Furthermore, high CD47 expression in tumor cells is associated with poor clinical outcomes (20,22,23).…”

Relationship between tumor-associated macrophage subsets and CD47 expression in squamous cell carcinoma of the head and neck in the tumor microenvironment

“…10,15 Although an appropriate mAb to assess CD47 protein expression in formalin-fixed paraffin-embedded (FFPE) human samples does not currently exist, several recent studies performed immunohistochemical (IHC) analyses on human tumor samples using polyclonal antibodies against CD47. 16,17 In addition to the expression of CD47 by cancer cells, the roles of M2 in TME have been comprehensively investigated; however, the relationship between the expression of CD47 in cancer tissues and macrophage subsets in the peritumoral area remains unclear. Zhang et al 18 previously reported migratory, but not phagocytic activity in relation to the expression of CD47 and the M1/M2 context with a series of CD47 IHC analyses on patients with malignancies; however, differences in the potential and mechanisms underlying phagocytosis by M1 and M2 in relation to the expression of CD47 or dynamisms among macrophage subsets in TME have not yet been elucidated in detail.…”