Estrogen suppression of erb B2 expression is associated with increased growth rate of ZR‐75‐1 human breast cancer cells in vitro and in nude mice

Amplification and enhanced expression of the erb B2/HER‐2/ neu gene has been associated with an increased growth rate and poor prognosis of human breast cancer. We have studied the relationship between erb B2 expression and the regulation of cell growth by estrogen and anti‐estrogens in the human breast cancer cell line ZR‐75‐1 in vitro and in athymic nude mice, pS2 being used as a marker gene for estrogen‐stimulated gene expression. Only low amounts of erb B2 mRNA were seen in the cells grown in vitro in the presence of estrogen which stimulated the cells to proliferate rapidly and induced the expression of pS2 mRNA. Upon hormone withdrawal, erb B2 mRNA and protein increased, while pS2 mRNA declined to an undetectable level and cell proliferation slowed down. Opposite but more rapid changes were observed upon estrogen addition. The anti‐estrogens toremifene and tamoxifen inhibited estrogen induction of pS2 expression, down‐regulation of erb B2 expression and proliferation of the ZR‐75‐1 cells in a concentration‐ dependent manner. Similar results were obtained in nude mice. ZR‐75‐1 cells formed tumors only in mice carrying estrogen pellets. In these tumors little erb B2 mRNA was seen. Concomitant administration of toremifene or tamoxifen increased erb B2 mRNA and abolished pS2 mRNA. Our results show that enhanced expression of erb B2 is associated with hormone deprivation and growth arrest of the estrogen‐dependent breast cancer cell line ZR‐75‐1. Thus, in mammary epithelial cells, erb B2 may have important estrogen‐regulated functions which are not related to cell proliferation.