Abstract
Understanding the initiation and progression of breast cancer requires knowledge of the normal development of the mammary ductal network. We have developed a platform based on primary human breast tissue grown in a highly‐defined, 3D mammary explant system, which faithfully recapitulates the normal morphogenesis of human mammary ducts. This system allows for the study of signaling cues that regulate normal development. Strikingly, although different HER1 ligands all permit ductal development, they generate different distinct patterns of cell fate. The intensity of signaling through the ERK1/2‐RSK signaling pathways alters cell fate decisions by progenitor populations within the duct. EGF causes an expansion of basal cells whereas amphiregulin enables normal lineage specification. In EGF conditions inhibition of RSK restores normal ductal development. These findings are relevant to triple negative breast cancer (TNBC) in which increased RSK signaling is observed, and thus RSK may play a role in the inappropriate expansion of the basal population that occurs in some types of TNBC. Identifying the cell‐autonomous and extrinsic cues that regulate ductal development will aid in identifying novel drug targets for breast cancer.
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