Vulnerability of Normal Human Mammary Epithelial Cells to Oncogenic Transformation.

摘要

Breast tumor cells display great diversity in gene and protein expression, and genomic alterations, associated with striking differences in clinical parameters. Our approach to understanding the molecular pathways that lead to the different types of breast cancer in vivo has been to model this process in vitro. Thus far, almost all in vitro transformed HMEC lines represent a limited subset of in vivo cancer phenotypes. We hypothesized that this could result from restrictive and stressful culture conditions that don t support growth of the target cells. Our proposal has sought to generate lines more reflective of breast cancer phenotypes by using our less stressful HMEC culture methods that support long-term growth of cells of luminal, basal, and progenitor lineages, and to directly examine the effects of stress on vulnerability to oncogenic transformation. We have now shown that unstressed cells are more vulnerable to c-Myc and TERT induced transformation, that different early-stage pathways to transformation are associated with distinct molecular properties, and that normal cells from older women have altered lineage markers that may make their luminal cells more vulnerable to transformation. In the process, we have generated, and continue to characterize, new transformed HMEC lines that exhibit a greater diversity of phenotypes including luminal, progenitor and claudin low as well as basal.