| Abstract: |
The majority (75%) of human breast cancers express estrogen receptor (ER). Although ER-positive tumors usually respond to antiestrogen therapies, 30% of them do not. It is not known what controls the ER status of breast cancers or their responsiveness to antihormone interventions. In this report, we document that transgenic (TG) expression of Wnt-1 in mice induces ER-positive tumors. Loss of Pten or gain of Ras mutations during the evolution of tumors in Wnt-1 TG mice has no effect on the expression of ER, but overexpression of Neu or loss of p53 leads to ER-negative tumors. Thus, our results provide compelling evidence that expression of ER in breast cancer may be influenced by specific genetic changes that promote cancer progression. These findings constitute a first step to explore the molecular mechanisms leading to ER-positive or ER-negative mammary tumors. In addition, we find that ER-positive tumors arising in Wnt-1 TG mice are refractory to both ovariectomy and the ER antagonist tamoxifen, but lose ER expression with tamoxifen, suggesting that antiestrogen selects for ER-negative tumor cells and that the ER-positive cell fraction is dispensable for growth of these tumors. This is a first report of a mouse model of antiestrogen-resistant ER-positive breast cancers, and could provide a powerful tool to study the molecular mechanisms that control antiestrogen resistance. © 2005 Nature Publishing Group. All rights reserved. |
| Keywords: |
immunohistochemistry; signal transduction; controlled study; protein expression; intercellular signaling peptides and proteins; genetics; cancer growth; nonhuman; mouse; animal; animals; mice; animal tissue; gene overexpression; breast cancer; phosphatase; ovariectomy; epidermal growth factor receptor 2; animal experiment; animal model; estrogen; drug effect; drug resistance; drug resistance, neoplasm; protein tyrosine kinase; breast neoplasms; protein p53; physiology; transgenic mouse; mus musculus; mice, transgenic; animal disease; disease model; gene expression regulation; tumor suppressor gene; gene expression regulation, neoplastic; biosynthesis; drug mechanism; signal peptide; breast tumor; tumor suppressor proteins; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; tamoxifen; cell fractionation; receptor, erbb-2; receptors, estrogen; protein-tyrosine kinases; molecular interaction; experimental neoplasm; antineoplastic agents, hormonal; estrogen receptor; disease models, animal; tumor suppressor protein; wnt proteins; wnt protein; phosphoric monoester hydrolases; oncogene ras; pten protein, human; antineoplastic hormone agonists and antagonists; wnt1 protein; antiestrogen; hormone resistance; genes, p53; wnt; mitogenic agent; mitogens; oncogene neu; mouse model; mammary neoplasms, animal; wnt1 protein, human; wnt1 protein, mouse
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