Our research interest is to understand the molecular mechanisms of action of steroid hormone, estrogen. The homeodynamic regulation of estrogen target tissue physiology relies on transient fluctuations in estrogen levels that are sensed by target organs that reply to hormone through a complex array of convergent and divergent signaling pathways. These pathways orchestrate cellular proliferation, differentiation and death that result in target tissue-specific responses. The flow of estrogen information is primarily conveyed by the transcription factors, estrogen receptors (ERs) a and b. The estrogen bound ERs mediate many nuclear and cytoplasmic events. One nuclear estrogen signaling involves the interaction of ERs with specific DNA sequences within gene promoters, known as estrogen responsive elements (EREs). ERs subsequently recruits co-activators/regulators to initiate local chromatin remodeling and to bridge with general transcription factors, thereby enabling gene transcription. This pathway is called the ERE-dependent estrogen-ER signaling. Although ERs display similar biochemical functions, they differ in their mode of transcription in the ERE-dependent signaling pathway. ERs also regulate gene expression by tethering to a transcription factor bound to its cognate regulatory element on DNA. This is the DNA-dependent and ERE-independent signaling pathway that also responds to ERs differently. Furthermore, the membrane/cytoplasmic ERs can elicit distinct responses by associating with, and modifying the functions of, a variety of proximal signaling molecules.
Utilizing a multidisciplinary approach that includes biochemistry, molecular, cellular, and tumor biology, one focus of our research is to address the basis for the distinct transcription mode of ERs in order to provide a functional characterization of the ERaand ERb subtypes. We also use structurally modified ER subtypes and various in vitro and in situexperimental models to focus on the dissection of estrogen signaling pathways to elucidate the relative importance of each pathway in physiology and pathophysiology of target tissue functions. A better conceptualization of regulatory mechanisms for estrogen signaling is pivotally important to understand the initiation and progression of estrogen target tissue malignancies that result from the uncoupling of regulatory mechanisms involved in cell proliferation and death. This recognition is providing us with an additional research focus that deals with the development of novel receptor-based modalities for the prevention and treatment of estrogen target tissue cancers.