PROGRESSION OF MCF-7 BREAST-CANCER CELLS TO ANTIESTROGEN-RESISTANT PHENOTYPE IS ACCOMPANIED BY ELEVATED LEVELS OF AP-1 DNA-BINDING ACTIVITY

We have isolated a variant of the MCF-7 human breast tumor that is cha racterized by a hormone-independent, yet hormone-responsive, phenotype , This tumor, designated MCF-WES, was derived from MCF-7 tumor cells i mplanted in the mammary fat pad of a nude mouse in the absence of estr adiol supplementation. MCF-WES tumors remain responsive to estradiol; however, unlike the parental MCF-7 tumors, they are stimulated to grow by tamoxifen, Additionally, MCF-WES cells are resistant to the pure s teroidal antiestrogen, ICI 182,780. To our knowledge, a tumor with thi s combination of properties has not yet been described. Nuclear estrog en receptor (ER) levels in MCF-WES cells were 10% of those for MCF-7 u nder steroid-depleted conditions, MCF-WES tumor ER levels were 32% of those in MCF-7 tumors. Similarly, in vivo expression of ER mRNA for MC F-WES was 20% of levels determined for MCF-7, Further characterization of MCF-WES cells showed that they have increased levels of AP-1 DNA-b inding activity, The marked increase in AP-1 binding activity may act to bypass the hormone dependence that is a characteristic of MCF-7 cel ls, it is also probable that the increase in AP-1 binding activity is responsible for the finding that MCF-WES cells secrete greater quantit ies of metalloproteinase activity in comparison to parental MCF-7 cell s, suggesting progression to a more invasive, malignant phenotype, Mor e complete characterization of this new cell line will help elucidate hormone-independent breast cancer and possibly identify targets for th erapy.