Estrogen Signaling in Breast Tumorigenesis
CitationChi, David. 2016. Estrogen Signaling in Breast Tumorigenesis. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractThe estrogen receptor (ER) is expressed in approximately 70% of sporadic breast cancers and is believed to activate genes driving tumorigenesis and initial cell proliferation. Therapeutic targeting of the ER signaling pathway has proven effective, but tumor relapse and endocrine resistance are not uncommon with metastatic disease then ensuing. Various reproductive endocrine modulations can alter the lifetime risk of developing breast cancer, and ER-targeting agents such as tamoxifen and raloxifene are effective in greatly reducing the risk of breast cancer. At the same time, ER and other steroid hormone receptors are crucial for proper development and differentiation of the mammary gland. The genomic interactions underlying normal ER signaling and its subsequent changes during tumorigenesis are thus poorly understood. Here the transcriptomic and cistromic effects of estrogen stimulation in human primary mammary epithelial cells are described to be markedly different from its known roles in ER-driven breast cancer. In the normal mammary epithelial context, estrogen stimulation has a drastically muted global genomic response compared to its previously observed functions in breast cancer. Notably, ER activation does not promote cellular proliferation in normal mammary epithelial cells, and the loss of putative E2-induced tumor suppressors and gain of ER-mediator oncogenes can be a driving mechanism for breast tumorigenesis. This cellular reprogramming of the ER signaling network may then alter the functioning phenotype of normal mammary epithelial cells and and be sufficient for the loss of normal ER function and gain of its oncogenic functions. Unraveling ER signaling in the normal mammary epithelium in contrast to its functions in breast cancer will enhance our understanding of breast tumorigenesis and metastatic progression and aid the development of more effective prevention strategies and targeted therapeutics.
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