Selection of Early-Occurring Mutations Dictates Hormone-Independent Progressionin Mouse Mammary TumorLines

Abstract

Mice harboring three mouse mammary tumor virus (MMTV) variants develop pregnancy-dependent (PD) tumors that progress to pregnancy-independent (PI) behavior through successive passages. Herein, we identified 10 predominant insertions in PI transplants from 8 independent tumor lines. These mutations were also detected in small cell populations in the early PD passages. In addition, we identified a new viral insertion upstream of the gene Rspo3 , which is overexpressed in three of the eight independent tumor lines and codes for a protein very similar to the recently described protein encoded by Int7 . This study suggests that during progression towards hormone independence, clonal expansion of cells with specific mutations might be more relevant than the occurrence of new MMTV insertions.