title: Progression of MCF-7 breast cancer cells to antiestrogen-resistant phenotype is accompanied by elevated levels of AP-1 DNA-binding activity.
abstract: We have isolated a variant of the MCF-7 human breast tumor that is characterized by a hormone-independent, yet hormone-responsive, phenotype. This tumor, designated MCF-WES, was derived from MCF-7 tumor cells implanted in the mammary fat pad of a nude mouse in the absence of estradiol 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 steroidal antiestrogen, ICI 182,780. To our knowledge, a tumor with this combination of properties has not yet been described. Nuclear estrogen receptor (ER) levels in MCF-WES cells were 10% of those for MCF-7 under steroid-depleted conditions. MCF-WES tumor ER levels were 32% of those in MCF-7 tumors. Similarly, in vivo expression of ER mRNA for MCF-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-binding activity. The marked increase in AP-1 binding activity may act to bypass the hormone dependence that is a characteristic of MCF-7 cells. It is also probable that the increase in AP-1 binding activity is responsible for the finding that MCF-WES cells secrete greater quantities of metalloproteinase activity in comparison to parental MCF-7 cells, suggesting progression to a more invasive, malignant phenotype. More complete characterization of this new cell line will help elucidate hormone-independent breast cancer and possibly identify targets for therapy.
authors.affiliation: Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Dumont
authors.forename: A J
authors.initials: AJ
authors.lastname: Bitonti
authors.forename: C D
authors.initials: CD
authors.lastname: Wallace
authors.forename: R J
authors.initials: RJ
authors.lastname: Baumann
authors.forename: E A
authors.initials: EA
authors.lastname: Cashman
authors.forename: D E
authors.initials: DE
authors.lastname: Cross-Doersen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division; D004273:DNA, Neoplasm / Q000032:analysis / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D000077267:Fulvestrant; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010641:Phenotype; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis / Q000235:genetics; D011980:Receptors, Progesterone / Q000032:analysis; D013629:Tamoxifen / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D004965:Estrogen Antagonists; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D018808:Transcription Factor AP-1; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D018093:Gelatinases