Induction of phenotypic changes in HER2-postive breast cancer cells in vivo and in vitro

Abstract

The influence of breast cancer cells on normal cells of the microenvironment, such as fibroblasts and macrophages, has been heavily studied but the influence of normal epithelial cells on breast cancer cells has not. Here using in vivo and in vitro models we demonstrate the impact epithelial cells and the mammary microenvironment can exert on breast cancer cells. Under specific conditions, signals that originate in epithelial cells can induce phenotypic and genotypic changes in cancer cells. We have termed this phenomenon "cancer cell redirection." Once breast cancer cells are redirected, either in vivo or in vitro, they lose their tumor forming capacity and undergo a genetic expression profile shift away from one that supports a cancer profile towards one that supports a non-tumorigenic epithelial profile. These findings indicate that epithelial cells and the normal microenvironment influence breast cancer cells and that under certain circumstances restrict proliferation of tumorigenic cells.

The Influence of the Normal Mammary Microenvironment on Breast Cancer Cells

“…However, the ratio of normal cells (MECS) to cancer cells will control cancer cell redirection in transplantations. A summary of these findings can be seen in Table 1 [15,16,30,31].…”

“…HER2+ breast cancer cells and epithelial cells were cultured either alone or in ratios of 1:1 or 1:50, respectively. When cultured alone, HER2 + breast cancer cells expressed both HER2 and phospho-HER2 [15]. The breast epithelial cells do not express noticeable levels of HER2 or phospho-HER2 in vitro [15].…”

“…A stem cell niche comprises the microenvironment that encircles stem cells and the immediate cellular activity through short and long distances [14,15]. The mammary microenvironment contains several important aspects, including stem cells, neighboring signaling cells, supporting stroma, extracellular matrix (ECM), and intercellular signals that regulate stem and signaling cells [5,6].…”

“…The mammary microenvironment contains several important aspects, including stem cells, neighboring signaling cells, supporting stroma, extracellular matrix (ECM), and intercellular signals that regulate stem and signaling cells [5,6]. Various cell types comprise the normal mammary niche, including epithelial cells, myoepithelial cells, adipocytes, nerve cells, endothelial cells, and fibroblasts [14][15][16]. Immune cells, such as macrophages, are common as well [14].…”

“…However, the ratio of normal cells (MECS) to cancer cells will control cancer cell redirection in transplantations. A summary of these findings can be seen in Table 1 [15,16,30,31]. The same animal model for cancer cell redirection was used in order to establish cancer cell redirection using human cancer cells.…”