Potential of endogenous estrogen receptor beta to influence the selective ER modulator ERbeta complex

Int J Oncol. 2005 Aug;27(2):327-35.

Abstract

The ratio of estrogen receptor beta (ERbeta) to ERalpha can alter the estrogen-like properties of tamoxifen. Transient transfection of ERbeta cDNA into cells can decrease the estrogen-like properties of the ERalpha:tamoxifen complex, whereas an increase in the amount of ERbeta is associated with tamoxifen-resistant breast cancer. We have addressed each of these hypotheses by examining well characterized laboratory models. We determined whether changes in endogenous ERbeta are responsible for the estrogen-like or antiestrogenic properties of tamoxifen or raloxifene in MDA-MB-231 cells transfected with cDNAs for ERalpha or mutants D351G, D351Y. We found that the amount of ERbeta mRNA in separate, stable transfectants of mutant ERalpha cDNA was always < 2% of ERalpha. Since at least a 50:50 mixture of ERalpha:ERbeta is needed to silence the tamoxifen:ERalpha complex, we conclude that insufficient ERbeta mRNA is available for selective ER modulation in stable transfectants of D351G and D351Y ERalpha. Similarly, to test the hypothesis that ERbeta is up-regulated and plays an important role during the development of tamoxifen-stimulated tumor growth, we quantitatively analyzed ERbeta and ERalpha mRNA in tamoxifen-naïve (MCF-7:E2, ECC1:E2) and tamoxifen-stimulated tumors (MCF-7:TAM, EnCa 101:TAM). We found that ERbeta mRNA levels were not significantly elevated in tamoxifen-stimulated tumors and the ERalpha mRNA remained over 99% out of all ER species for all the tumors tested. The same results were also obtained when mRNA levels of ERbeta and ERalpha in a series of tamoxifen-naïve and tamoxifen-resistant breast cancer was analyzed. We conclude that endogenous ERbeta may not play a dominant role in the modulation of the tamoxifen ERalpha complex, or in the development of tamoxifen-stimulated resistant tumor growth.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA, Complementary / chemistry
  • DNA, Complementary / genetics
  • Drug Resistance, Neoplasm
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation, Missense
  • Ovariectomy
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Raloxifene Hydrochloride / metabolism
  • Raloxifene Hydrochloride / pharmacology
  • Reproducibility of Results
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Selective Estrogen Receptor Modulators / metabolism*
  • Selective Estrogen Receptor Modulators / pharmacology
  • Sequence Analysis, DNA
  • Tamoxifen / metabolism*
  • Tamoxifen / pharmacology
  • Transfection
  • Xenograft Model Antitumor Assays

Substances

  • DNA, Complementary
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • RNA, Messenger
  • Selective Estrogen Receptor Modulators
  • Tamoxifen
  • Raloxifene Hydrochloride