PubMed:12114443 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/12114443","sourcedb":"PubMed","sourceid":"12114443","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/12114443","text":"The effect of second-line antiestrogen therapy on breast tumor growth after first-line treatment with the aromatase inhibitor letrozole: long-term studies using the intratumoral aromatase postmenopausal breast cancer model.\nPURPOSE: The aromatase inhibitors letrozole and anastrozole have been approvedrecently as first-line treatment options for hormone-dependent advanced breast cancer. Although it is established that a proportion of patients who relapse on first-line tamoxifen therapy show additional responses to aromatase inhibitors, it has not been determined whether tumors that acquire resistance to aromatase inhibitors in the first line remain sensitive to second-line therapy with antiestrogens. The aim of this study was to determine whether aromatase-transfected and hormone-dependent MCF-7Ca human breast cancer cells remain sensitive to antiestrogens after: (a) long-term growth in steroid-depleted medium in vitro; and (b) long-term treatment with the aromatase inhibitor letrozole in vivo.\nMETHODS: In the first approach, a variant of the MCF-7Ca human breast cancer cell line was selected that had acquired the ability to grow in estrogen-depleted medium after 6-8 months of culture. Steroid-deprived UMB-1Ca cells were analyzed for aromatase activity levels, hormone receptor levels, and sensitivity to estrogens and antiestrogens in vitro and in vivo. In the second approach, established MCF-7Ca breast tumor xenografts were treated with letrozole 10 microg/day for 12 weeks followed by 100 microg/day for 25 weeks until tumors acquired the ability to proliferate in the presence of the drug. Long-term letrozole-treated tumors were then transplanted into new mice, and the effects of antiestrogens and aromatase inhibitors on tumor growth were determined.\nRESULTS: Steroid-deprived UMB-1Ca breast cancer cells continued to express aromatase activity at levels comparable with the parental cell line. However, compared with MCF-7Ca cells, UMB-1Ca cells expressed elevated levels of functionally active estrogen receptor. The growth of UMB-1Ca cells in vitro was inhibited by the antiestrogens tamoxifen and faslodex and tumor growth in vivo was inhibited by tamoxifen. In the second approach, the time for MCF-7Ca tumor xenografts to approximately double in volume after being treated sequentially with the increasing doses of letrozole was thirty-seven weeks. Long-term letrozole-treated tumors continued to express functionally active aromatase. When transplanted into new mice, growth of the long-term letrozole-treated tumors was slowed by tamoxifen and inhibited more effectively by faslodex. Tumor growth was refractory to the aromatase inhibitors anastrozole and formestane but, surprisingly, showed sensitivity to letrozole.\nCONCLUSIONS: Steroid-deprived UMB-1Ca human breast cancer cells selected in vitro and long-term letrozole-treated MCF-7Ca breast tumor xenografts remain sensitive to second-line therapy with antiestrogens and, in particular, to faslodex. This finding is associated with increased expression of functionally active estrogen receptor after steroid-deprivation of MCF-7Ca human breast cancer cells in vitro.","tracks":[{"project":"PubmedHPO","denotations":[{"id":"T1","span":{"begin":374,"end":387},"obj":"HP_0003002"},{"id":"T2","span":{"begin":374,"end":387},"obj":"HP_0100013"},{"id":"T3","span":{"begin":381,"end":387},"obj":"HP_0002664"},{"id":"T4","span":{"begin":576,"end":582},"obj":"HP_0002664"},{"id":"T5","span":{"begin":814,"end":827},"obj":"HP_0003002"},{"id":"T6","span":{"begin":814,"end":827},"obj":"HP_0100013"},{"id":"T7","span":{"begin":821,"end":827},"obj":"HP_0002664"}],"attributes":[{"subj":"T1","pred":"source","obj":"PubmedHPO"},{"subj":"T2","pred":"source","obj":"PubmedHPO"},{"subj":"T3","pred":"source","obj":"PubmedHPO"},{"subj":"T4","pred":"source","obj":"PubmedHPO"},{"subj":"T5","pred":"source","obj":"PubmedHPO"},{"subj":"T6","pred":"source","obj":"PubmedHPO"},{"subj":"T7","pred":"source","obj":"PubmedHPO"}]},{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":3069,"end":3086},"obj":"gene:2099"},{"id":"T1","span":{"begin":3130,"end":3143},"obj":"disease:C0006142"},{"id":"T2","span":{"begin":3069,"end":3086},"obj":"gene:2099"},{"id":"T3","span":{"begin":3130,"end":3143},"obj":"disease:C0678222"}],"relations":[{"id":"R1","pred":"associated_with","subj":"T0","obj":"T1"},{"id":"R2","pred":"associated_with","subj":"T2","obj":"T3"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"attributes":[{"subj":"T0","pred":"source","obj":"DisGeNET"},{"subj":"T1","pred":"source","obj":"DisGeNET"},{"subj":"T2","pred":"source","obj":"DisGeNET"},{"subj":"T3","pred":"source","obj":"DisGeNET"}]},{"project":"DisGeNET5_gene_disease","denotations":[{"id":"12114443-16#76#93#gene2099","span":{"begin":3069,"end":3086},"obj":"gene2099"},{"id":"12114443-16#137#150#diseaseC0006142","span":{"begin":3130,"end":3143},"obj":"diseaseC0006142"},{"id":"12114443-16#137#150#diseaseC0678222","span":{"begin":3130,"end":3143},"obj":"diseaseC0678222"}],"relations":[{"id":"76#93#gene2099137#150#diseaseC0006142","pred":"associated_with","subj":"12114443-16#76#93#gene2099","obj":"12114443-16#137#150#diseaseC0006142"},{"id":"76#93#gene2099137#150#diseaseC0678222","pred":"associated_with","subj":"12114443-16#76#93#gene2099","obj":"12114443-16#137#150#diseaseC0678222"}],"attributes":[{"subj":"12114443-16#76#93#gene2099","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"12114443-16#137#150#diseaseC0006142","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"12114443-16#137#150#diseaseC0678222","pred":"source","obj":"DisGeNET5_gene_disease"}]},{"project":"PubMed_Structured_Abstracts","denotations":[{"id":"T1","span":{"begin":233,"end":1008},"obj":"OBJECTIVE"},{"id":"T2","span":{"begin":1018,"end":1778},"obj":"METHODS"},{"id":"T3","span":{"begin":1788,"end":2754},"obj":"RESULTS"},{"id":"T4","span":{"begin":2768,"end":3159},"obj":"CONCLUSIONS"}],"attributes":[{"subj":"T1","pred":"source","obj":"PubMed_Structured_Abstracts"},{"subj":"T2","pred":"source","obj":"PubMed_Structured_Abstracts"},{"subj":"T3","pred":"source","obj":"PubMed_Structured_Abstracts"},{"subj":"T4","pred":"source","obj":"PubMed_Structured_Abstracts"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"PubmedHPO","color":"#e293ec","default":true},{"id":"DisGeNET","color":"#93ecc8"},{"id":"DisGeNET5_gene_disease","color":"#ecae93"},{"id":"PubMed_Structured_Abstracts","color":"#9493ec"}]}]}}