Increasing the number of tandem estrogen response elements increases the estrogenic activity of a tamoxifen analogue

doi:10.1016/0304-3835(95)03755-L

Cancer Letters

Volume 92, Issue 1, 25 May 1995, Pages 39-47

https://doi.org/10.1016/0304-3835(95)03755-L Get rights and content

Abstract

There have been several reports of women who have tumor relapse while on tamoxifen therapy, followed by tumor regression after tamoxifen withdrawal. In such apparently tamoxifen-stimulated tumors, there is likely a genetic change which increases the estrogenicity of tamoxifen. In this study, we determine if increasing the number of estrogen response elements (EREs) in the promotor region of a reporter gene can alter the agonistic activity of fixed-ring 4-hydroxytamoxifen. We show that increasing the number of EREs in the promotor region increases the transcriptional response of the reporter plasmid to estradiol. We also find that while fixed-ring 4-hydroxytamoxifen is unable to stimulate transcription when one ERE is present, transcriptional activation can occur with multiple EREs. These results demonstrate that ERE amplification could explain the agonistic properties of tamoxifen, and suggests a novel mechanism to explain tamoxifen-stimulated breast cancer growth.

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Citation Excerpt :
The expression vector coding for GSTP (GenBank Accession No. NM_000852.3) was generated by inserting the 0.6 kbp long full-length GSTP into the EcoRI/BamHI sites of pIRESneo vector (Clontech, Mountain View, CA) to produce the pIRESneo/GSTP plasmid. The ERE-luciferase plasmid contains three copies of the Xenopus laevis vitellogenin A2 ERE upstream of the fire fly luciferase [13] and is a gift from Dr. V.C. Jordan (Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC). The pSG5 plasmid containing the wild-type human ERα was originally engineered by Professor P. Chambon (Institut National de la Sante et de la Recherche Medicale, Strasbourg, France).
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Increasing the number of tandem estrogen response elements increases the estrogenic activity of a tamoxifen analogue

Abstract

Arch. Intern. Med.

Nature

EMBO. J.

J. Biol. Chem.

Br. J. Cancer

EMBO J.

Gene

Mol. Endocrinol.

Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31 000 recurrences and 24 000 deaths among 75 000 women

Lancet

Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31 000 recurrences and 24 000 deaths among 75 000 women

Lancet

Tamoxifen-induced tumor stimulation and withdrawal response

Cancer Treat. Rep.

Clinical significance of tamoxifen withdrawal response

Lancet

Response after withdrawal of tamoxifen and progestogens in advanced breast cancer

Ann. Oncol.

Structure-activity relationships of antioestrogens with regard to interaction with 17 β-estradiol in the mouse uterus and vagina

Acta Endocrinol.

Tamoxifen is a potent “pure” antioestrogen in the chick oviduct

Nature

Characterization of tamoxifen stimulated MCF-7 tumor variants grown in athymic mice

Breast Cancer Res. Treat.

The estrogen receptor from a tamoxifen-stimulated MCF-7 tumor variant contains a point mutation in the ligand-binding domain

Breast Cancer Res. Treat.

Investigation of the mechanism of tamoxifen-stimulated breast tumor growth with non-isomerizable analogues of tamoxifen and metabolites

J. Natl. Cancer. Inst.

The oestrogen receptor: from perception to mechanism