RANK Induces Epithelial–Mesenchymal Transition and Stemness in Human Mammary Epithelial Cells and Promotes Tumorigenesis and Metastasis

Abstract

Paracrine signaling through receptor activator of NF-kB (RANK) pathway mediates the expansion of mammary epithelia that occurs during pregnancy, and activation of RANK pathway promotes mammary tumorigenesis in mice. In this study we extend these previous data to human cells and show that the RANK pathway promotes the development of mammary stem cells and breast cancer. Overexpression of RANK (FL-RANK) in a panel of tumoral and normal human mammary cells induces the expression of breast cancer stem and basal/stem cell markers. High levels of RANK in untransformed MCF10A cells induce changes associated with both stemness and transformation, including mammary gland reconstitution, epithelial-mesenchymal transition (EMT), increased migration, and anchorage-independent growth. In addition, spheroids of RANK overexpressing MCF10A cells display disrupted acinar formation, impair growth arrest and polarization, and luminal filling. RANK overexpression in tumor cells with nonfunctional BRCA1 enhances invasiveness in acinar cultures and increases tumorigenesis and metastasis in immunodeficient mice. High levels of RANK were found in human primary breast adenocarcinomas that lack expression of the hormone receptors, estrogen and progesterone, and in tumors with high pathologic grade and proliferation index; high RANK/RANKL expression was significantly associated with metastatic tumors. Together, our findings show that RANK promotes tumor initiation, progression, and metastasis in human mammary epithelial cells by increasing the population of CD44 þ CD24À cells, inducing stemness and EMT. These results suggest that RANK expression in primary breast cancer associates with poor prognosis. Cancer Res; 72(11); 2879-88. Ó2012 AACR.

Receptor Activator for NF-κB Ligand in Acute Myeloid Leukemia: Expression, Function, and Modulation of NK Cell Immunosurveillance

“…Recent studies suggested an involvement of RANKL in disease pathophysiology of chronic lymphoid leukemia (CLL) and multiple myeloma as well as metastatic spread of solid tumors (19)(20)(21)(22)(23)(24)(25)32), but nothing was yet known on the role of the RANK-RANKL molecule system in AML. In this study, we analyzed RANKL expression on primary AML cells by flow cytometry and selected malignant cells among PBMCs of leukemia patients by staining for CD33 and CD34.…”

“…The TNFR family member receptor activator for NF-kB (RANK; TNFRSF11A) and its ligand (receptor activator for NF-kB ligand; RANKL) are mainly known for their key role in regulating bone metabolism (15,16) but were also found to influence the interaction of dendritic cells (DCs) and T cells as well as the pathophysiology of hematopoietic malignancies and metastasis of solid tumors (17)(18)(19)(20)(21)(22)(23)(24)(25). Notably, available data indicate that RANK is also expressed on NK cells (26), but to date nothing is known regarding the functional relevance of RANK-RANKL interaction for NK cell reactivity.…”

Progesterone signalling in breast cancer: a neglected hormone coming into the limelight

“…I hypothesize that repeated activation of these pathways during the luteal phase of menstrual cycles promotes breast carcinogenesis. Some of these such as amphiregulin 98 , receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) 99 and inhibitor of DNA binding 4 (ID4) 100 have indeed been implicated in the genesis of distinct human breast cancer subtypes. Interfering pharmacologically with menstrual cycle-induced activation of the breast (as described above), may be of particular use in young patients with breast cancer.…”

Tumor stem cells in breast cancer

“…-/low СОК [27]. Межклеточные и клеточно-матриксные взаимодей-ствия крайне важны для поддержания и выживания СОК при метастазировании.…”