Pure Antiestrogens The Most Important Advance in the Endocrine Therapy of Breast Cancer since 1896?<sup><i>a</i></sup>

Nicholson, Robert Ian; Gee, Julia Margaret Wendy; Bryant, Sian; Francis, A; McClelland, Richard Andrew; Knowlden, Janice Mary; Wakeling, A. E.; Osborne, C. Kent

doi:10.1111/j.1749-6632.1996.tb16247.x

Cited by 12 publications

(8 citation statements)

References 42 publications

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“…Epidemiological studies demonstrate a causative role for estrogen exposure in the etiology of breast cancer (2), whereas the clinical efficacy of oophorectomy and pharmacological agents that inhibit the synthesis or action of estrogen further emphasize the fundamental importance of estrogeninduced mitogenesis in breast cancer (51). It is now evident, however, that estrogens do not exert their mitogenic actions alone but act in concert with other hormones, growth factors, and cytokines to regulate breast epithelial cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Insulin/Insulin-like Growth Factor-I and Estrogen Cooperate to Stimulate Cyclin E-Cdk2 Activation and Cell Cycle Progression in MCF-7 Breast Cancer Cells through Differential Regulation of Cyclin E and p21WAF1/Cip1

Lai

Šarčević

Prall

et al. 2001

Journal of Biological Chemistry

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Estrogens and insulin/insulin-like growth factor-I (IGF-I) are potent mitogens for breast epithelial cells and, when co-administered, induce synergistic stimulation of cell proliferation. To investigate the molecular basis of this effect, a MCF-7 breast cancer cell model was established where serum deprivation and concurrent treatment with the pure estrogen antagonist, ICI 182780, inhibited growth factor and estrogen action and arrested cells in G 0 /G 1 phase. Subsequent stimulation with insulin or IGF-I alone failed to induce significant Sphase entry. However, these treatments increased cyclin D1, cyclin E, and p21 gene expression and induced the formation of active Cdk4 complexes but resulted in only minor increases in cyclin E-Cdk2 activity, likely due to recruitment of the cyclin-dependent kinase (CDK) inhibitor p21 WAF1/Cip1 into these complexes. Treatment with estradiol alone resulted in a greater increase in cyclin D1 gene expression but markedly decreased p21 expression, with a concurrent increase in Cdk4 and Cdk2 activity and subsequent synchronous entry of cells into S phase. Co-administration of insulin/ IGF-I and estrogen induced synergistic stimulation of S-phase entry coincident with synergistic activation of high molecular mass (ϳ350 kDa) cyclin E-Cdk2 complexes lacking p21. To determine if the ability of estrogen to deplete p21 was central to these effects, cells stimulated with insulin and estradiol were infected with an adenovirus expressing p21. Induction of p21 to levels equivalent to those following treatment with insulin alone markedly inhibited the synergism between estradiol and insulin on S-phase entry. Thus the ability of estradiol to antagonize the insulin-induced increase in p21 gene expression, with consequent activation of cyclin E-Cdk2, is a central component of the synergistic stimulation of breast epithelial cell proliferation induced by simultaneous activation of the estrogen and insulin/IGF-I signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Insulin/Insulin-like Growth Factor-I and Estrogen Cooperate to Stimulate Cyclin E-Cdk2 Activation and Cell Cycle Progression in MCF-7 Breast Cancer Cells through Differential Regulation of Cyclin E and p21WAF1/Cip1

Lai

Šarčević

Prall

et al. 2001

Journal of Biological Chemistry

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“…DISCUSSION Pure antiestrogens have been shown to interfere with one of the most important systems regulating the biology of hormonedependent breast cancer cells, namely, the IGF-I system (de Cupis and Favoni, 1997; Nicholson et al, 1996). The compounds inhibit IGF-induced proliferation, which is associated with, i.e., downregulation of IGF binding sites and reduction of IGF availability.…”

Section: Long-term Ici 182780 Treatment Does Not Affect Shc Signalingmentioning

confidence: 99%

IGF-IR Signaling in Breast Cancer

Surmacz¹

2000

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“…The pure steroidal antiestrogens are thus of great interest. Not only do they block both transcription-activating domains of the ER and have pure antiestrogenic activity on transcription of most, if not all, genes that have been studied, but they also induce loss of ER from the cell (Dauvois et al 1992, Nicholson et al 1996. Cultured cells, breast tumors from in vivo experimental model systems, and tumors from people, have been shown to have markedly lower ER levels after treatment with ICI 182,780.…”

Section: Optimal Endocrine Therapymentioning

confidence: 99%

Aromatase inhibitors in relation to other forms of endocrine therapy for breast cancer.

Osborne¹

1999

Endocrine-Related Cancer

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Most endocrine therapies for breast cancer inhibit tumor growth by depriving the cell of estrogen or by blocking its receptor. However, some drugs, such as tamoxifen, can bind to the estrogen receptor (ER) and have both estrogenic and antiestrogenic effects, depending on the tissue, cell, or promoter context. These mixed properties may be explained by new information on ER function at the molecular level. Whether a synthetic drug acts as an estrogen or antiestrogen on a specific gene may be dictated by the particular ensemble of ER subtype, receptor interacting proteins, other transcription factors, or specific elements within the promoter of estrogen-regulated genes. Alterations in these other factors may also play a role in resistance to hormonal therapies. Aromatase inhibitors, like ovarian ablation, inhibit growth by lowering the estrogen concentration in blood or in the tumor tissue itself. Aromatase inhibitors are effective even in postmenopausal women with low estrogen concentrations -probably because of the ability of the tumor to become hypersensitive to estrogen after prolonged estrogen deprivation. Given that the ER itself is the prime target for endocrine manipulation, the ideal endocrine therapy may be one that reduces or eliminates ER from the tumor cell. Pure steroidal antiestrogens are then of great interest because, not only do they inhibit ER-induced transactivation of estrogen regulated genes, they also induce ER degradation. Additional clinical trials are necessary to identify Endocrine-Related Cancer (1999) 6 271-276 the optimal endocrine therapy and optimal sequence of available therapies.

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Pure Antiestrogens The Most Important Advance in the Endocrine Therapy of Breast Cancer since 1896?^a

Cited by 12 publications

References 42 publications

Insulin/Insulin-like Growth Factor-I and Estrogen Cooperate to Stimulate Cyclin E-Cdk2 Activation and Cell Cycle Progression in MCF-7 Breast Cancer Cells through Differential Regulation of Cyclin E and p21WAF1/Cip1

Insulin/Insulin-like Growth Factor-I and Estrogen Cooperate to Stimulate Cyclin E-Cdk2 Activation and Cell Cycle Progression in MCF-7 Breast Cancer Cells through Differential Regulation of Cyclin E and p21WAF1/Cip1

IGF-IR Signaling in Breast Cancer

Aromatase inhibitors in relation to other forms of endocrine therapy for breast cancer.

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Pure Antiestrogens The Most Important Advance in the Endocrine Therapy of Breast Cancer since 1896?a

Cited by 12 publications

References 42 publications

Insulin/Insulin-like Growth Factor-I and Estrogen Cooperate to Stimulate Cyclin E-Cdk2 Activation and Cell Cycle Progression in MCF-7 Breast Cancer Cells through Differential Regulation of Cyclin E and p21WAF1/Cip1

Insulin/Insulin-like Growth Factor-I and Estrogen Cooperate to Stimulate Cyclin E-Cdk2 Activation and Cell Cycle Progression in MCF-7 Breast Cancer Cells through Differential Regulation of Cyclin E and p21WAF1/Cip1

IGF-IR Signaling in Breast Cancer

Aromatase inhibitors in relation to other forms of endocrine therapy for breast cancer.

Contact Info

Product

Resources

About

Pure Antiestrogens The Most Important Advance in the Endocrine Therapy of Breast Cancer since 1896?^a