DEREGULATED ESTROGEN RECEPTOR ALPHA-INITIATED PRENEOPLASIA AND ITS PROGRESSION: ROLE OF STAT5A AND CYCLIN D1
Miermont, Anne M.
Furth, Priscilla A
Deregulation of estrogen pathway has been linked to the pathophysiology of breast cancer. CERM (Conditional Estrogen Receptor alpha in Mammary epithelium) mice with deregulated ERalpha (ER) in the mammary epithelium develop ductal carcinoma in situ (DCIS) with nuclear STAT5A and increased cyclinD1 expression. STAT5A, as well as ER and cyclinD1 play an unclear role in breast cancer. Genetic studies were carried out to determine their role in the development and progression of ER-initiated DCIS.STAT5A and ER or PR were in the same nuclei of some human DCIS. However, DCIS progressed in neither CERM nor CERM/Stat5a-/- mice. In contrast, CERM mice developed hyperplastic alveolar nodules (HANs), which prevalence was abrogated by loss of two Stat5a alleles independent of proliferation and apoptosis. Upon carcinogenic insult, loss of two Stat5a alleles played a deregulated ER-dependent dual role on the prevalence of HANs but not of DCIS and mammary adenocarcinoma. Indeed, ER(-) and ER(+) adenocarcinomas developed in CERM/Stat5a-/- and Stat5a-/- mice. During normal mammary gland development, CERM/Stat5a-/- mice demonstrated delayed differentiation of their terminal end buds, which did not correlate with an increased carcinogenic susceptibility. In summary, STAT5A played a complex role in ER-initiated tumorigenesis and this is the first evidence that STAT5A and ER can interact in vivo in the mammary gland with biological significance.Whereas multiple HANs development significantly increased only in CERM/D1, ER(+) and ER( ) mammary adenocarcinomas developed in CERM and CERM/D1 mice. Tamoxifen did not alter the pattern of disease in CERM, CERM/D1, D1 and WT mice but significantly increased the prevalence of multiple HANs in CERM mice and led to the development of ER(-), cyclinD1(+) mammary cancers in the CERM and CERM/D1 mice. Gain of cyclinD1 did not seem to add carcinogenic risk to deregulated ER; however, DMBA significantly increased the prevalence of multiple HANs in CERM mice. In summary, gain of cyclinD1 did not significantly increase the effects of deregulated ER on tumorigenesis supporting the hypothesis that cyclinD1 acts downstream of ER. Moreover, we have developed a breast cancer mouse model with deregulated ER (CERM) that developed ER(-) and ER(+) and cyclinD1(+) cancers and that could be used to study the origins of ER( ) cancers and to test anti-cyclinD1 therapies.
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Divekar, Shailaja Dilip (Georgetown University, 2008)ABSTRACT Growth factors are thought to activate estrogen receptor-alpha ERα by phosphorylating the serines in the N-terminus of the receptor. However, this mechanism does not account for the conformational changes that ...