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

Abstract

Breast cancer is a heterogeneous disease. In particular, triple-negative breast cancer (TNBC) comprises various molecular subgroups with unclear identities and currently has few targeted treatment options. Our previous study identified protein C receptor (Procr) as a surface marker on mammary stem cells (MaSCs) located in the basal layer of the normal mammary gland. Given the possible connection of TNBC with basal layer stem cells, we conducted comparative analyses of Procr in breast cancers of mouse and human origin. In mouse mammary tumors, we showed that Procr + cells are enriched for cancer stem cells (CSCs) in Wnt1 basal-like tumors, but not in Brca1 basal-like tumors or PyVT luminal tumors. In human cancers, PROCR was robustly expressed in half of TNBC cases. Experiments with patient-derived xenografts (PDXs) revealed that PROCR marks CSCs in this discrete subgroup (referred to as PROCR + TNBC). Interfering with the function of PROCR using an inhibitory nanobody reduced the CSC numbers, arrested tumor growth and prevented rapid tumor recurrence. Our data suggest a key role of MaSC in breast tumorigenesis. Moreover, our work indicates that PROCR can be used as a biomarker to stratify TNBC into clinically relevant subgroups and may provide a novel targeted treatment strategy for this clinically important tumor subtype.

Predicting cell-to-cell communication networks using NATMI

“…Examining the basal cell data in more detail identified 9 receptors (Gpc1, Procr, Fzd7, Itga5, Ldlr, Tlr2, Lrp6, Ephb1, and Tfrc) and 8 ligands (Tgfa, Ngf, Col5a2, Il11, Col4a2, Jag1, Col18a1 and Hspg2) at least twofold down-regulated at 18 months ( Supplementary Data 8). Notably, many of these top downregulated ligands and receptors are known to be important in maintenance of normal mammary basal stem cells and are implicated in basal-like and triple negative breast cancer [43][44][45][46][47][48][49][50][51] .…”

Nanobodies: Next Generation of Cancer Diagnostics and Therapeutics

“…Notably, Rossotti et al ( 57 ) reported DNA immunization-raised EGFR nanobodies with improved functionality compared to protein immunization-raised nanobodies. Nanobodies targeting EGF ( 58 ), HER2 ( 59 , 60 ), CAIX ( 61 ), death receptor 5 (DR5) ( 62 , 63 ), c-Met ( 64 , 65 ), HGF ( 66 ), AgSK1 ( 67 ), mesothelin ( 68 ), proteasome activator complex PA28 ( 69 ), ephrin receptor A4 (EphA4) ( 70 ), CEA-cell adhesion molecule-6 (CEACAM6) ( 71 ), mitochondrial translation elongation factor (TUFM) ( 72 ), protein C receptor ( 73 ), Wnt receptors (LRP5/6) ( 74 ), and CD33 ( 75 ) have also demonstrated delayed tumor growth.…”

Halting triple negative breast cancer by targeting PROCR

“…Whether PROCR plays an analogous role in normal human breast tissue remains unknown but its expression is confined to the basal layer. 6 Extending their study to specimens from breast cancer patients, Wang et al next showed that PROCR was highly expressed in approximately half of TNBCs in their patient cohorts. Notably, there was an inverse correlation between PROCR hi and BRCA1 mutant TNBCs.…”

“…The study by Wang et al has significantly clarified this area through identification of PROCR as a specific marker of CSCs in TNBCs. 6 They first compared the tumor-initiating capacity of Procr + tumor cells in three different mouse models of breast cancer. Although Procr was expressed on a small subset of tumor cells in all models, it specifically enriched for CSCs in the Wnt1driven transgenic model, which harbors an expanded population of stem-like cells.…”

“…Functional studies via shRNA knockdown or CRISPR/CAS9 knockout revealed that PROCR is essential for the growth of PDX tumors. 6 To explore the effect of targeting PROCR function using a more clinically feasible strategy, Wang et al developed an inhibitory nanobody against an extracellular region of PROCR. This antibody proved to be very effective as a single agent in delaying tumor growth in recipient mice transplanted with PROCR + cells isolated from breast tumors, when treatment was commenced shortly after engraftment.…”