Antiestrogen Resistance in Human Breast Cancer

Pavlik, Edward J.; Nelson, K. D.; Srinivasan, Suseela; DePriest, Paul D.; Kenady, Daniel E.

doi:10.1007/978-1-4612-2306-1_5

Estrogens, Progestins, and Their Antagonists 1997

DOI: 10.1007/978-1-4612-2306-1_5

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Antiestrogen Resistance in Human Breast Cancer

Edward J. Pavlik¹,

K. D. Nelson²,

Suseela Srinivasan³

et al.

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1999

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Cited by 2 publications

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“…ICI 182,780 also interferes with growth factor‐induced growth, but it is not clear whether this activity is mediated exclusively through the ER, or if some ER‐independent mechanism is implicated (de Cupis et al, 1995). Despite their great antitumor effects, pure antiestrogens do not circumvent the development of antiestrogen resistance, as most breast tumor cells initially sensitive to ICI 182,780 eventually become unresponsive to the drug (de Cupis and Favoni, 1997; Pavlik et al, 1996; Nicholson et al, 1995). The mechanism of this resistance is not clear, but it has been suggested that both mutations of the ER as well as alterations in growth factor‐dependent mitogenic pathways may be involved (de Cupis and Favoni, 1997; Larsen et al, 1997; Pavlik et al, 1996; Wiseman et al, 1993).…”

mentioning

confidence: 99%

Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells

et al. 1999

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The pure antiestrogen ICI 182,780 inhibits insulin‐like growth factor (IGF)‐dependent proliferation in hormone‐responsive breast cancer cells. However, the interactions of ICI 182,780 with IGF‐I receptor (IGF‐IR) intracellular signaling have not been characterized. Here, we studied the effects of ICI 182,780 on IGF‐IR signal transduction in MCF‐7 breast cancer cells and in MCF‐7‐derived clones overexpressing either the IGF‐IR or its 2 major substrates, insulin receptor substrate 1 (IRS‐1) or src/collagen homology proteins (SHC). ICI 182,780 blocked the basal and IGF‐I‐induced growth in all studied cells in a dose‐dependent manner; however, the clones with the greatest IRS‐1 overexpression were clearly least sensitive to the drug. Pursuing ICI 182,780 interaction with IRS‐1, we found that the antiestrogen reduced IRS‐1 expression and tyrosine phosphorylation in several cell lines in the presence or absence of IGF‐I. Moreover, in IRS‐1‐overexpressing cells, ICI 182,780 decreased IRS‐1/p85 and IRS‐1/GRB2 binding. The effects of ICI 182,780 on IGF‐IR protein expression were not significant; however, the drug suppressed IGF‐I‐induced (but not basal) IGF‐IR tyrosine phosphorylation. The expression and tyrosine phosphorylation of SHC as well as SHC/GRB binding were not influenced by ICI 182,780. In summary, downregulation of IRS‐1 may represent one of the mechanisms by which ICI 182,780 inhibits the growth of breast cancer cells. Thus, overexpression of IRS‐1 in breast tumors could contribute to the development of antiestrogen resistance. Int. J. Cancer 81:299–304, 1999. © 1999 Wiley‐Liss, Inc.

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mentioning

confidence: 99%

Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells

et al. 1999

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“…ICI 182,780 also interferes with growth factor-induced growth, but it is not clear whether this activity is mediated exclusively through the ER, or if some ER-independent mechanism is implicated (de Cupis et al, 1995). Despite their great antitumor effects, pure antiestrogens do not circumvent the development of antiestrogen resistance, as most breast tumor cells initially sensitive to ICI 182,780 eventually become unresponsive to the drug (de Cupis and Favoni, 1997;Pavlik et al, 1996;Nicholson et al, 1995). The mechanism of this resistance is not clear, but it has been suggested that both mutations of the ER as well as alterations in growth factordependent mitogenic pathways may be involved (de Cupis and Favoni, 1997;Larsen et al, 1997;Pavlik et al, 1996;Wiseman et al, 1993).…”

mentioning

confidence: 99%

Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells

Salerno,

Sisci,

Mauro

et al. 1999

Int. J. Cancer

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The pure antiestrogen ICI 182,780 inhibits insulin-like growth factor (IGF)-dependent proliferation in hormoneresponsive breast cancer cells. However, the interactions of ICI 182,780 with IGF-I receptor (IGF-IR) intracellular signaling have not been characterized. Here, we studied the effects of ICI 182,780 on IGF-IR signal transduction in MCF-7 breast cancer cells and in MCF-7-derived clones overexpressing either the IGF-IR or its 2 major substrates, insulin receptor substrate 1 (IRS-1) or src/collagen homology proteins (SHC). ICI 182,780 blocked the basal and IGF-I-induced growth in all studied cells in a dose-dependent manner; however, the clones with the greatest IRS-1 overexpression were clearly least sensitive to the drug. Pursuing ICI 182,780 interaction with IRS-1, we found that the antiestrogen reduced IRS-1 expression and tyrosine phosphorylation in several cell lines in the presence or absence of IGF-I. Moreover, in IRS-1overexpressing cells, ICI 182,780 decreased IRS-1/p85 and IRS-1/GRB2 binding. The effects of ICI 182,780 on IGF-IR protein expression were not significant; however, the drug suppressed IGF-I-induced (but not basal) IGF-IR tyrosine phosphorylation. The expression and tyrosine phosphorylation of SHC as well as SHC/GRB binding were not influenced by ICI 182,780. In summary, downregulation of IRS-1 may represent one of the mechanisms by which ICI 182,780 inhibits the growth of breast cancer cells. Thus, overexpression of IRS-1 in breast tumors could contribute to the development of antiestrogen resistance.

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Antiestrogen Resistance in Human Breast Cancer

Cited by 2 publications

References 195 publications

Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells

Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells

Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells

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