Breast Cancer Intra-Tumor Heterogeneity: One Tumor, Different Entities

In recent years, it has become evident that intra-tumor heterogeneity of breast cancer is a big challenge for the diagnosis, treatment, and clinical course of tumor-bearing patients. The advances in molecular biology and other technologies have led to the knowledge that a breast cancer tumor is comprised of multiple cellular entities. Here we review the two theories that have been described, trying to explain the origin of intra-tumor heterogeneity: clonal evolution and cancer stem cells. The first one considers that a single cell gives rise to many subpopulations through the accumulation of multiple aberrations, while the cancer stem cells theory foresees a hierarchical tumor evolution where only a few cells with self-renewal capacity give rise to different subpopulations. We also analyze the genetic, epigenetic, and microenvironment contributions to breast cancer intra-tumor heterogeneity. Finally, the clinical and therapeutic impact of intra-tumor heterogeneity on the outcome of breast cancer patients is discussed.