A Novel Approach to Inactivate the Estrogen Receptor
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Estrogen interacts with the estrogen receptor (ER) to regulate a variety of genes critical for cell growth and tissue development. Through the interaction with ER, estrogens can promote the survival and growth of breast tumor in nearly two-thirds of postmenopausal patients with breast cancer. Currently, anti-estrogens (SERMs) used to treat breast cancer by blocking the interaction of estrogens with the ER. However, studies have found that SERMs partially activate ER in certain tissues. The undesirable activation of ER in these tissues often lead to side effects, including blood clots. Also, many patients become resistant to SERM treatment after several years of therapy. Therefore, developing improved therapy or identifying additional targets to inactive ER activity in breast tumor cells remains critical. A region of the estrogen receptor, known as the ligand-binding domain (LBD), keeps the receptor "inactive" in the absence of estrogen. Understanding the mechanism by which LBD keeps ER inactive may advance the development of effective therapy and overcome the resistance difficulties associated with current breast cancer treatments.
 
 
 
 
 
 
 
 Previous research from many labs has shown that a regulatory protein complex, Hsp90-complex, attaches to the inactive form of ER by binding to the LBD. Upon ER activation through estrogen binding, the Hsp90-complex detaches from the LBD. Also, the Hsp90-complex has been found to negatively correlate with some ER activities. This has led to the hypothesis for this project that the binding of Hsp90-complex to the LBD of estrogen receptor keeps the receptor inactive. We further postulate that by maintaining estrogen receptor in an inactive form, the Hsp90-complex may suppress the growth of tumor breast cells. We will test these hypotheses in this research study. 
 
 
 
 
 
 
 
 Estrogen receptor generally controls a variety of genes to promote growth of breast tumors. However, gene regulation experiments can be complicated. Thus, our approach to study the inactivation function of the LBD is to physically link the LBD to the -lactamase enzyme. This allows us to use enzymatic experiments and circumvents the complications involved in gene regulation approaches. Using this strategy combined with genetic and biochemical analyses, we will examine the level of -lactamase activity fused to the LBD in the presence and absence of the Hsp90-complex. If the Hsp90-complex is involved in the inactivation function of the LBD, a lower -lactamase activity would be observed in the presence of this complex. These studies will therefore indicate whether the Hsp90-complex assists the LBD to inactivate ER activity. Furthermore, we hope to identify additional factors (proteins) that enhance the inactivation function of the LBD. This will be done using genetic screens performed in yeast. Finally, the factors identified in the genetics screens and the Hsp90-complex will be examined in breast cancer cells to determine whether they can inhibit the growth of breast tumor cells.
 
 
 
 
 
 
 
 Although it has been well established that the LBD inactivates ER activity, the mechanism remains elusive. By examining the involvement of the Hsp90-complex and identifying factors that assist the LBD to inactivate ER, this study may also provide additional targets for breast cancer treatment.