Protein C receptor stimulates multiple signaling pathways in breast cancer cells

Abstract

The protein C receptor (PROCR) has emerged as a stem cell marker in several normal tissues and has also been implicated in tumor progression. However, the functional role of PROCR and the signaling mechanisms downstream of PROCR remain poorly understood. Here, we dissected the PROCR signaling pathways in breast cancer cells. Combining protein array, knockdown, and overexpression methods, we found that PROCR concomitantly activates multiple pathways. We also noted that PROCR-dependent ERK and PI3k-Akt-mTOR signaling pathways proceed through Src kinase and transactivation of insulin-like growth factor 1 receptor (IGF-1R). These pathway activities led to the accumulation of c-Myc and cyclin D1. On the other hand, PROCR-dependent RhoA-ROCK-p38 signaling relied on coagulation factor II thrombin receptor (F2R). We confirmed these findings in primary cells isolated from triple-negative breast cancer-derived xenografts (PDX) that have high expression of PROCR. To the best our knowledge, this is the first comprehensive study of PROCR signaling in breast cancer cells, and its findings also shed light on the molecular mechanisms of PROCR in stem cells in normal tissue.

Fluorescence imaging of a potential diagnostic biomarker for breast cancer cells using a peptide-functionalized fluorogenic 2D material

“…4). A human TNBC cell line (MDA-MB-231) known to highly express the protein 26 and another breast cancer cell line (MCF-7) with a lower PROCR expression level 27 were used. We first determined that with an increasing concentration of TAMRA-AN33, the fluorescence produced in MDA-MB-231 cells was gradually enhanced (Fig.…”

Protein C receptor is a therapeutic stem cell target in a distinct group of breast cancers

“…MDA-MB-231, to investigate the relationship between PROCR and CSCs has been proven not suitable, because almost all MDA-MB-231 cells exhibit high PROCR expression. 23 The separation of PROCR + and PROCR − cells amongst MDA-MB-231 cells in previous studies may have been compromised by the inefficacy of antibody used for FACS analysis. 28,29 In this study, using PDX samples, we propose that PROCR + cells are CSCs in PROCR + BC subtypes, defined by the following functional assays for CSCs.…”

“…S6b). 23 Here, we investigated the mechanism of action of the PROCR inhibitory nanobody. In culture, the inhibitory effects on pSrc, pIGF-1R and all of the known PROCR-dependent intracellular signaling activities were evident by 12 h following the nanobody treatment, and became more pronounced by 16 h (Fig.…”

“…The expression of PROCR was also investigated in a panel of human breast cancer cell lines in our previous study. 23 qPCR analysis showed that all ER + /PR + lines (T-47D, ZR75-1, MDA-MB-415 and MCF-7) and HER2 + lines (SK-BR-3, MDA-MB-453 and BT474) exhibited relatively low PROCR expression. A subset of TNBC lines (MDA-MB-231, Hs578T, HCC38, CAL51 and HCC1806) highly expressed PROCR, whereas some TNBC lines (MDA-MB-468, BT549, MDA-MB-436, HCC1937, HCC1599 and HCC2157) exhibited low expression of PROCR.…”

Halting triple negative breast cancer by targeting PROCR

“…8 Genetic lineage tracing using mouse models mimicking PROCR + TNBC will help determine whether PROCR + stem cells can serve as cells of origin of cancer. PROCR has previously been shown by this group to regulate a complex set of signaling pathways including MEK-ERK, PI3K-AKT-mTOR and RhoA-ROCK, 9 but the key pathways activated by this single-pass transmembrane receptor and those necessary for conferring CSC features remain to be elucidated. Interestingly, PROCR is a Wnt target gene 8 and gain-of-function mutations in β-catenin or inactivating mutations in APC result in enhanced Wnt signaling in diverse cancer types, although these mutations do not play a prominent role in breast cancer.…”