Molecular and cellular alterations associated with long-term murine mammary cancer prevention following short-term tamoxifen chemoprevention indicate luminal progenitor cells as targets

Limited term administration of tamoxifen for 2-8 years results in long-term prevention of estrogen receptor positive (ER+) breast cancer as demonstrated in several clinical trials. How the memory of tamoxifen is initiated and maintained, as well as which cells are involved and what molecular messages are transmitted, is undefined. Understanding these features of this robust chemopreventive agent will lead to significant advancement in our knowledge of how a healthy breast environment is supported. The purpose of this study was to determine the molecular message that reflects a long-term and efficacious memory of tamoxifen. We used microarrays to identify genes with a significant long-term alteration in expression level following a short-term exposure to tamoxifen as a chemopreventive. A total of 20 samples were analyzed, 10 from tamoxifen treated animals and 10 from placebo treated animals. One number 4 mammary gland was isolated and used in preparation of the microarray probe 30 days after the completion of treatment. Animals were monitored for mammary tumor formation up to 2 years of age following collection of the microarray sample gland and tumor outcome was scored. Statistical comparisons of gene expression were made between animals that presented with tumor formation (10 animals) and those that did not form tumors (10 animals) up to 2 years of age.