Selective activation of estrogen receptor-β transcriptional pathways by an herbal extract

Aleksandra Cvoro, Sreenivasan Paruthiyil, Jeremy O. Jones, Christina Tzagarakis-Foster, Nicola J. Clegg, Deirdre Tatomer, Roanna T. Medina, Mary Tagliaferri, Fred Schaufele, Thomas (Tom) Scanlan, Marc I. Diamond, Isaac Cohen, Dale C. Leitman

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Novel estrogenic therapies are needed that ameliorate menopausal symptoms and have the bone-sparing effects of endogenous estrogens but do not promote breast or uterine cancer. Recent evidence suggests that selective activation of the estrogen receptor (ER)-β subtype inhibits breast cancer cell proliferation. To establish whether ERβ-selective ligands represent a viable approach to improve hormone therapy, we investigated whether the estrogenic activities present in an herbal extract, MF101, used to treat hot flashes, are ERβ selective. MF101 promoted ERβ, but not ERα, activation of an estrogen response element upstream of the luciferase reporter gene. MF101 also selectively regulates transcription of endogenous genes through ERβ. The ERβ selectivity was not due to differential binding because MF101 binds equally to ERα and ERβ. Fluorescence resonance energy transfer and protease digestion studies showed that MF101 produces a different conformation in ERα from ERβ when compared with the conformations produced by estradiol. The specific conformational change induced by MF101 allows ERβ to bind to an estrogen response element and recruit coregulatory proteins that are required for gene activation. MF101 did not activate the ERα-regulated proliferative genes, c-myc and cyclin D1, or stimulate MCF-7 breast cancer cell proliferation or tumor formation in a mouse xenograft model.Ourresults demonstrate that herbal ERβ-selective estrogens may be a safer alternative for hormone therapy than estrogens that nonselectively activate both ER subtypes.

Original languageEnglish (US)
Pages (from-to)538-547
Number of pages10
JournalEndocrinology
Volume148
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

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Estrogen Receptors
Estrogens
Response Elements
Breast Neoplasms
Cell Proliferation
Hormones
Hot Flashes
Fluorescence Resonance Energy Transfer
Uterine Neoplasms
myc Genes
Cyclin D1
Complementary Therapies
Luciferases
Reporter Genes
Heterografts
Transcriptional Activation
Digestion
Estradiol
Peptide Hydrolases

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Cvoro, A., Paruthiyil, S., Jones, J. O., Tzagarakis-Foster, C., Clegg, N. J., Tatomer, D., ... Leitman, D. C. (2007). Selective activation of estrogen receptor-β transcriptional pathways by an herbal extract. Endocrinology, 148(2), 538-547. https://doi.org/10.1210/en.2006-0803

Selective activation of estrogen receptor-β transcriptional pathways by an herbal extract. / Cvoro, Aleksandra; Paruthiyil, Sreenivasan; Jones, Jeremy O.; Tzagarakis-Foster, Christina; Clegg, Nicola J.; Tatomer, Deirdre; Medina, Roanna T.; Tagliaferri, Mary; Schaufele, Fred; Scanlan, Thomas (Tom); Diamond, Marc I.; Cohen, Isaac; Leitman, Dale C.

In: Endocrinology, Vol. 148, No. 2, 02.2007, p. 538-547.

Research output: Contribution to journalArticle

Cvoro, A, Paruthiyil, S, Jones, JO, Tzagarakis-Foster, C, Clegg, NJ, Tatomer, D, Medina, RT, Tagliaferri, M, Schaufele, F, Scanlan, TT, Diamond, MI, Cohen, I & Leitman, DC 2007, 'Selective activation of estrogen receptor-β transcriptional pathways by an herbal extract', Endocrinology, vol. 148, no. 2, pp. 538-547. https://doi.org/10.1210/en.2006-0803
Cvoro A, Paruthiyil S, Jones JO, Tzagarakis-Foster C, Clegg NJ, Tatomer D et al. Selective activation of estrogen receptor-β transcriptional pathways by an herbal extract. Endocrinology. 2007 Feb;148(2):538-547. https://doi.org/10.1210/en.2006-0803
Cvoro, Aleksandra ; Paruthiyil, Sreenivasan ; Jones, Jeremy O. ; Tzagarakis-Foster, Christina ; Clegg, Nicola J. ; Tatomer, Deirdre ; Medina, Roanna T. ; Tagliaferri, Mary ; Schaufele, Fred ; Scanlan, Thomas (Tom) ; Diamond, Marc I. ; Cohen, Isaac ; Leitman, Dale C. / Selective activation of estrogen receptor-β transcriptional pathways by an herbal extract. In: Endocrinology. 2007 ; Vol. 148, No. 2. pp. 538-547.
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