Aug. 30, 2013 — Researchers at the University of Cincinnati (UC) have identified a key protein as the first dual-function co-regulator of an estrogen receptor that plays a crucial role in cancer development, opening the way to improved therapeutic targets for several types of cancer such as breast, prostate, lung and brain cancer.
Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner
Background: The interactions between estrogen receptor β (ERβ1) and different coregulators are responsible for the distinct functions of ERβ1.
Results: Tip60 enhances ERβ1 transactivation at the AP-1 site but inhibits it at ERE sites.
Conclusion: Tip60 is either a coactivator or a corepressor for ERβ1 in a regulatory element-dependent manner.
Significance: Tip60 is the first multifaceted coregulator of the transcriptional activity of ERβ1 that has been identified.
The research was led by Shuk-Mei Ho, PhD, Jacob G. Schmidlapp Chair of Environmental Health and Professor at the UC College of Medicine and director of the Cincinnati Cancer Center, a collaborative initiative of UC, UC Health and Cincinnati Children’s Hospital Medical Center. It was published in The Journal of Biological Chemistry, appearing in the Aug. 30, 2013, issue.
Ho and her team focused on the interactions between estrogen receptor beta (ERβ1) and a co-regulator known as Tip60. Co-regulators are proteins that interact with transcription factors, which are proteins that bind to specific DNA sequences. Co-regulators can be co-activators, which activate gene transcription, or co-repressors, which repress gene transcription.
Unlike estrogen receptor alpha, which plays a role in breast cancer initiation and progression, estrogen receptor beta is a potent tumor suppressor. Co-activating estrogen receptor beta would impair cell growth, thereby halting or slowing the development of cancer. Co-repressing estrogen receptor beta would promote cell growth and therefore encourage tumor development.
Using in vitro models, the team found that Tip60 served as both a co-activator and a co-repressor of estrogen receptor beta, depending on the DNA site involved. Specifically, it served as a co-activator at the binding site known as activation protein 1 (AP-1) but a co-repressor at the estrogen response element (ERE) site.
“For suppression of tumor growth — for example, in cancer treatment — the goal would be to bring Tip60 to estrogen receptor beta as a partnership with any genes that contain an AP-1 site,” says Ho. “Therefore, we would want to design new drugs or identify natural products that accomplish this.”
Ho notes that the drug fulvestrant, commonly used in the treatment of breast cancer, augments co-activation of Tip60 at the AP-1 site. Plant-derived products such as flax seed, soybeans and tofu contain phytoestrogens that also activate Tip60 at the AP-1 site.
Adds Yuet-Kin Leung, PhD, assistant professor of environmental health at UC and second author of the study, “The important thing to do is to figure out how we can actually bring either a repressor to estrogen receptor beta or an activator to it so cell death activity can be increased or decreased.” (Promotion of cell growth, as opposed to the impairment of cell growth sought in tumor suppression, would be beneficial in such examples as wound healing or cardiovascular and brain injury repair, Leung notes.)
The Cincinnati Cancer Center encompasses the activities of University of Cincinnati Cancer Institute — one of four institutes of UC and UC Health — and the Cancer and Blood Diseases Institute at Cincinnati Children’s.
Members of the research team, in addition to Ho and Leung, included Pheruza Tarapore, PhD, assistant professor of environmental health; Ming-Tsung Lee, PhD, a recent graduate from the environmental health department; and Irving Chung, a former summer undergraduate research student.
The study was supported by grants from the National Institute of Environmental Health Sciences and the U.S. Department of Veterans Affairs.
Press release and photo courtesy of the University of Cincinnati Academic Health Center’s Health News, the school’s office of public relations and communications. You can find the original press release here.