Tamoxifen-resistant fibroblast growth factor-transfected MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI 182,780 and two aromatase inhibitors

Sandra W. McLeskey, Lurong Zhang, Dorraya El-Ashry, Bruce J. Trock, Cecilia A. Lopez, Samir Kharbanda, Christopher A. Tobias, Lori A. Lorant, Rachel S. Hannum, Robert B. Dickson, Francis G. Kern

Research output: Contribution to journalArticle

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Abstract

Although the antiestrogen tamoxifen has been the mainstay of therapy for estrogen receptor (ER)-positive breast cancer, successful treatment of responsive tumors is often followed by the acquisition of tamoxifen resistance. Subsequently, only 30-40% of patients have a positive response to second hormonal therapies. This lack of response might be explained by mechanisms for tamoxifen resistance that sensitize ER pathways to small amounts of estrogenic activity present in tamoxifen or that bypass ER pathways completely. To elucidate one possible mechanism of tamoxifen resistance, we treated ovariectomized tumor-bearing mice injected with fibroblast growth factor (FGF)-transfected MCF-7 breast carcinoma cells with the steroidal antiestrogen ICI 182,780 or one of two aromatase inhibitors, 4- OHA or letrozole. These treatments did not slow estrogen-independent growth or prevent metastasis of tumors produced by FGF-transfected MCF-7 cells in ovariectomized nude mice. FGF-transfected cells had diminished responses to ICI 182,780 in vitro, suggesting that autocrine activity of the transfected FGF may be replacing estrogen as a mitogenic stimulus for tumor growth. ER levels in FGF transfectants were not down-regulated, and basal levels of transcripts for estrogen-induced genes or of ER-mediated transcription of estrogen response element (ERE) luciferase reporter constructs in the FGF expressing cells were not higher than parental cells, implying that altered hormonal responses are not due to down-regulation of ER or to FGF-mediated activation of ER. These studies indicate that estrogen independence may be achieved through FGF signaling pathways independent of ER pathways. If so, therapies directed at the operative mechanism might produce a therapeutic response or allow a response to a second course of antiestrogen treatment.

Original languageEnglish
Pages (from-to)697-711
Number of pages15
JournalClinical Cancer Research
Volume4
Issue number3
StatePublished - Mar 1 1998
Externally publishedYes

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Aromatase Inhibitors
Estrogen Receptor Modulators
Fibroblast Growth Factors
MCF-7 Cells
Tamoxifen
Estrogen Receptors
Estrogens
letrozole
Therapeutics
Neoplasms
Breast Neoplasms
fulvestrant
Response Elements
Growth
Luciferases
Nude Mice
Down-Regulation
Neoplasm Metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

McLeskey, S. W., Zhang, L., El-Ashry, D., Trock, B. J., Lopez, C. A., Kharbanda, S., ... Kern, F. G. (1998). Tamoxifen-resistant fibroblast growth factor-transfected MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI 182,780 and two aromatase inhibitors. Clinical Cancer Research, 4(3), 697-711.

Tamoxifen-resistant fibroblast growth factor-transfected MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI 182,780 and two aromatase inhibitors. / McLeskey, Sandra W.; Zhang, Lurong; El-Ashry, Dorraya; Trock, Bruce J.; Lopez, Cecilia A.; Kharbanda, Samir; Tobias, Christopher A.; Lorant, Lori A.; Hannum, Rachel S.; Dickson, Robert B.; Kern, Francis G.

In: Clinical Cancer Research, Vol. 4, No. 3, 01.03.1998, p. 697-711.

Research output: Contribution to journalArticle

McLeskey, SW, Zhang, L, El-Ashry, D, Trock, BJ, Lopez, CA, Kharbanda, S, Tobias, CA, Lorant, LA, Hannum, RS, Dickson, RB & Kern, FG 1998, 'Tamoxifen-resistant fibroblast growth factor-transfected MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI 182,780 and two aromatase inhibitors', Clinical Cancer Research, vol. 4, no. 3, pp. 697-711.
McLeskey, Sandra W. ; Zhang, Lurong ; El-Ashry, Dorraya ; Trock, Bruce J. ; Lopez, Cecilia A. ; Kharbanda, Samir ; Tobias, Christopher A. ; Lorant, Lori A. ; Hannum, Rachel S. ; Dickson, Robert B. ; Kern, Francis G. / Tamoxifen-resistant fibroblast growth factor-transfected MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI 182,780 and two aromatase inhibitors. In: Clinical Cancer Research. 1998 ; Vol. 4, No. 3. pp. 697-711.
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abstract = "Although the antiestrogen tamoxifen has been the mainstay of therapy for estrogen receptor (ER)-positive breast cancer, successful treatment of responsive tumors is often followed by the acquisition of tamoxifen resistance. Subsequently, only 30-40{\%} of patients have a positive response to second hormonal therapies. This lack of response might be explained by mechanisms for tamoxifen resistance that sensitize ER pathways to small amounts of estrogenic activity present in tamoxifen or that bypass ER pathways completely. To elucidate one possible mechanism of tamoxifen resistance, we treated ovariectomized tumor-bearing mice injected with fibroblast growth factor (FGF)-transfected MCF-7 breast carcinoma cells with the steroidal antiestrogen ICI 182,780 or one of two aromatase inhibitors, 4- OHA or letrozole. These treatments did not slow estrogen-independent growth or prevent metastasis of tumors produced by FGF-transfected MCF-7 cells in ovariectomized nude mice. FGF-transfected cells had diminished responses to ICI 182,780 in vitro, suggesting that autocrine activity of the transfected FGF may be replacing estrogen as a mitogenic stimulus for tumor growth. ER levels in FGF transfectants were not down-regulated, and basal levels of transcripts for estrogen-induced genes or of ER-mediated transcription of estrogen response element (ERE) luciferase reporter constructs in the FGF expressing cells were not higher than parental cells, implying that altered hormonal responses are not due to down-regulation of ER or to FGF-mediated activation of ER. These studies indicate that estrogen independence may be achieved through FGF signaling pathways independent of ER pathways. If so, therapies directed at the operative mechanism might produce a therapeutic response or allow a response to a second course of antiestrogen treatment.",
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AU - Trock, Bruce J.

AU - Lopez, Cecilia A.

AU - Kharbanda, Samir

AU - Tobias, Christopher A.

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AU - Dickson, Robert B.

AU - Kern, Francis G.

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