Selective estrogen modulators as an anticancer tool: Mechanisms of efficiency and resistance

Surojeet Sengupta, V. Craig Jordan

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

The majority of breast cancers are estrogen receptor (ER) positive and depend on estrogen for growth. Therefore, blocking estrogen mediated actions remains the strategy of choice for the treatment and prevention of breast cancer. The selective estrogen receptor modulators (SERMs) are molecules that block estrogen action in breast cancer but can still potentially maintain the beneficial effects of estrogen in other tissues, such as bone and cardiovascular system. Tamoxifen, the prototypical drug of this class has been used extensively for the past 30 years to treat and prevent breast cancer. The target of drug action, ERs alpha and beta, are the two receptors which are responsible for the first step in estrogen and SERM action. The SERM binds to the ERs and confers a unique conformation to the complex. In a target site which expresses antiestrogenic actions, the conformation of the ER is distinctly different from estrogen bound ER. The complex recruits protein partners called corepressors to prevent the transcription of estrogen responsive genes. In contrast, at a predominantly estrogenic site coactivators for estrogen action are recruited. Unfortunately at an antiestrogenic site such as breast cancer, long term SERM therapy causes the development of acquired resistance. The breast and endometrial tumor cells selectively become SERM stimulated. Overexpression of receptor tyro sine kinases, HER-2, EGRF and IGRF and the signaling cascades following their activation are frequently involved in SERM resistant breast cancers. The aberrantly activated PI3K/AKT and MAPK pathways and their cross talk with the genomic components of the ER action are implicated in SERM resistance. Other down stream factors of HER-2 and EGRF signaling, such as PI3K/AKT, MAPK or mTOR pathways has also been found to be involved in resistance mechanisms. Blocking the actions of HER-2 and EGRF represent a rational strategy for treating SERM resistant phenotypes and may in fact restore the sensitivity to the SERMs. Another approach exploits the discovery that low dose estrogen will induce apoptosis in the SERM resistant breast cancers. Numerous clinical studies are addressing these issues.

Original languageEnglish (US)
Title of host publicationInnovative Endocrinology of Cancer
EditorsLev Berstein, Richard Santen
Pages206-219
Number of pages14
DOIs
StatePublished - 2008
Externally publishedYes

Publication series

NameAdvances in Experimental Medicine and Biology
Volume630
ISSN (Print)0065-2598

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