Emerging candidates in breast cancer stem cell maintenance, therapy resistance and relapse

Abstract

Therapy resistance is a major concern while treating breast cancer. Various mechanisms have been proposed, but so far nothing has been able to effectively address this problem. Accumulating evidences suggest that a subset of cancer cells provides survival benefits to the tumor and are responsible for therapy resistance and relapse of cancer. These so called the cancer stem cells, are known to be regulated by several pathways. Evidences shows that the tumor microenvironment plays a crucial role in maintaining the cancer stem cell pool. Signaling within the tumor is modulated by surrounding cells which secrete signals favoring tumor growth and metastasis. In breast cancer, the cancer stem cells have recently been reported to be influenced by tumor microenvironment via cytokines which act as chemoattractants for leukocytes. This review elucidates the emerging role of chemokine receptor and receptor activator of NFκB (RANK) ligand/RANK signaling pathways in mediating therapy resistance of breast cancer by maintaining the cancer stem cell pool.

Keywords: Breast cancer stem cells; NFκB (RANK) ligand; chemokines; therapy resistance.

Figure 1

Vicious cycle involving chemokine and RANK-RANKL signaling in the maintenance of breast cancer stem cells and chemotherapy resistance: 1) In the tumor microenvironment, upon chemotherapeutic treatment, stromal and cancer cells 2) release CXCR1/2 ligands which help in the 3) recruitment of neutrophils to the cancer site. CXCR1/2 ligands can also bind to their receptor, CXCR1/CXCR2, expressed by cancer cell or cancer stem cells providing survival benefits to them. 4) Neutrophils, through their proteases, cleave RANKL present on cancer cells or stromal cells, leading to the generation of soluble RANKL (sRANKL). 5) Released sRANKL binds to its receptor, RANK, present on cancer stem cells, leading to their 6) survival and maintenance in the presence of chemotherapy