Enhanced OCT4 Expression Imparts a Primitive Phenotype in Breast Cancer Cells and Explains Cancer Dormancy in Bone Marrow

PUBLIC ABSTRACT

Breast cancer (BC) remains a clinical dilemma, despite mammograms and early detection. It is believed that this is partly due to a subset of BC cells (BCCs) that survive in bone marrow (BM) as dormant cells. The study plans to explore the identity of the dormant BCCs in order to target them while they are in the BM with minimum toxicity to the endogenous BM cells. The study proposes that dormant BCCs overexpress two stem cell genes, REST and OCT4. These two genes can be regulated by another complex protein, NFêB, which is considered the master regulator of other genes that maintain dormancy. Inhibiting NFêB can reverse dormancy through silencing of REST and OCT4; consequently causing the BCCs to rapidly replicate and become sensitive to anti-cancer agents. REST and Oct4 are involved in maintaining stemness of cells and protection of tumors from undergoing cell death. Aim 1 will study if OCT4 is required for dormancy of the BCCs. Aim 2 will study if OCT4 and REST control the expressions by each other, and if they can be silenced by lowering the master regulator, NFêB. We will determine if silencing of NFêB will reverse dormancy and make the BCCs sensitive to anti-cancer agents. If successful, the studies will lead to other research that could cause direct targeting of dormant BCCs while they are close to the bone, with limited toxic effects on the cells in BM. The studies are relevant to all phases of BC, including the period of remission.