Biology and clinical applications of estrogen receptor beta isoforms in endocrine-related cancers.

摘要

Breast cancer (BCa) is the leading cause of cancer-related death in women worldwide, while prostate cancer (PCa) is the second-leading cause of cancer-related death in men in the U.S.A. We urge to understand molecular mechanisms of cancer progression in order to develop effective treatments. Both cancers are considered to be endocrine-related cancers because sex hormones are responsible for their tumorigenesis, and there is growing evidence estrogens play an important role in promoting PCa and BCa pathogenesis. Estrogen actions are mainly mediated through estrogen receptors (ERs), which are divided into 2 subtypes, a and ss1. Of these, ERss1 is known for its protective role in PCa and BCa due to its antiproliferative and proapoptotic actions. Recently, different splice variants of ERss1 have been discovered. Differential expression patterns and transcriptional activities of ERss1 and its isoforms in endocrine-related cancers revealed that they possess distinct functions. The purpose of my study is to understand the mechanisms of regulation and molecular actions of ERss1 and its isoforms. Chapter 1 gives a brief background on the development of PCa and BCa and the relationship between estrogens and their pathogenesis. The structure and molecular actions of estrogen receptors are described, while the roles of ERss1 and its isoforms in these cancers are also introduced. Chapter 2 focuses on the regulatory mechanisms of differential expression patterns of ERss1 and its isoforms, ERss2 and 5, during PCa progression. Our data shows that the expression of ERss1 is preferentially controlled by alternative promoter usage at transcriptional level, whereas that of ERss2 and 5 is determined by complex interplay between transcriptional and post-transcriptional regulation. Chapter 3 examines the modulation of ERss1 transcriptional activity by its coregulator, Tip60, at different DNA-binding sequences. Tip60 was found to be a dual-function coregulator of ERss1 in a cis-regulatory element-dependent manner. It enhanced ERss1 transactivation at activator protein 1 (AP-1) binding site but suppressed its transactivation at various estrogen response elements (EREs) in an estrogen-independent manner. Chapter 4 investigates a novel role of ERss5 in the apoptosis of BCa cells. It was shown to confer sensitivity of BCa cells to chemotherapeutic agent (doxorubicin and cisplatin)-induced apoptosis through its interaction with a Bcl-2 family member, Bcl2L12. Chapter 5 summarizes the results, experimental limitations, future directions, significance and perspective of the studies. Also, the prospect of using ERss1 and its isoforms as the therapeutic targets of PCa and BCa will be discussed. My thesis tries to provide more information about the molecular biology and clinical applications of ERss. I uncovered the mechanisms by which the distinct expression patterns of ERss isoforms are regulated during PCa progression. The differential transcriptional activity of ERss1 at different cis-regulatory sequences was shown to be determined by a dual-function coregulator. Moreover, a novel ERss5- and Bcl2L12-mediated apoptotic pathway in BCa cells was discovered. Collectively, my data reveal that ERss1 and its isoforms possess distinct regulatory mechanisms and signaling pathways which contribute to their unique functional roles in PCa and BCa.