Molecular Events Driving Luminal-A Breast Cancer Progression: Interactions Of Tumor Cells With An Integrative Tumor Microenvironment Stimulus

Luminal-A is the most prevalent breast cancer subtype. Although most Luminal-A patients initially have a favorable outcome, some of them become resistant to endocrine therapy and develop metastases. Our previous studies indicate that the tumor microenvironment (TME) is a major driver of this violent phenotype. To further investigate the effects of the TME, we have developed a stimulus of Luminal-A cells by factors that integrate three arms of the TME (called herein “TME-Stimulation”): hormonal, inflammatory and growth-stimulating. Following three days of stimulation by estrogen (representative of the hormonal arm), TNFα (pro-inflammatory) and EGF (growth-stimulating), human Luminal-A cells acquired a metastatic phenotype, evident both by in-vitro assays and in-vivo studies.

In addition to the invasive characteristics acquired by the Luminal-A breast tumor cells following TME-Stimulation, this stimulus has led to enrichment of CD44⁺/CD24^low/- cells in the population. While in unstimulated cells this sub-population was negligent, in TME-stimulated cells it increased significantly. CD44⁺/CD24^low/- are markers of cancer stem cells (CSCs) in breast cancer, having the potential to generate a heterogeneous population of tumor cells, increase therapy resistance and have an EMT-related phenotype; they are considered to constitute the tumor sub-population that initiates metastases, and therefore are also called tumor-initiating cells.

In our previous studies we have shown that the sub-population CD44⁺/CD24^low/- cells, that was enriched by TME-Stimulation of Luminal-A cells, indeed carried typical characteristics of CSCs (observations were made with two human Luminal-A cells, MCF-7 and T47D). We also demonstrated that this sub-population stood in the basis of metastasis formation in-vivo. Currently, our goal is to identify the molecular mechanisms through which TME-Stimulation leads to reprogramming of Luminal-A cells to CSCs. Understanding these processes will allow us to characterize key targets that may be relevant for therapy of Luminal-A patients.