Journal Article

Role of ERα in the differential response of Stat5a loss in susceptibility to mammary preneoplasia and DMBA-induced carcinogenesis

Anne M. Miermont, Angela R. Parrish and Priscilla A. Furth

in Carcinogenesis

Volume 31, issue 6, pages 1124-1131
Published in print June 2010 | ISSN: 0143-3334
Published online February 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq048
Role of ERα in the differential response of Stat5a loss in susceptibility to mammary preneoplasia and DMBA-induced carcinogenesis

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Deregulated estrogen signaling is evidently linked to breast cancer pathophysiology, although the role of signal transducer and activator of transcription (Stat)5a, integral to normal mammary gland development, is less clear. A mouse model of mammary epithelial cell-targeted deregulated estrogen receptor α (ERα) expression [conditional ERα in mammary epithelium (CERM)] was crossed with mice carrying a germ line deletion of Stat5a [Stat5a−/−] to investigate interactions between ERα and Stat5a in mammary tissue. CERM, CERM/Stat5a+/−, CERM/Stat5a−/−, Stat5a+/−, Stat5a−/− and wild-type (WT) mice were generated to test the roles of ERα and Stat5a on pubertal differentiation and cancer progression with and without exposure to the chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Only CERM/Stat5a−/− mice demonstrated delayed pubertal terminal end bud differentiation. Without DMBA exposure, Stat5a loss abrogated ERα-initiated hyperplastic alveolar nodule (HAN) development and, similarly, Stat5a−/− mice did not develop HANs. However, although Stat5a loss still reduced ERα-initiated HAN prevalence following DMBA exposure, Stat5a loss without deregulated ERα was associated with an increased HAN prevalence compared with WT. Progression to ERα(+) and ERα(−) adenocarcinoma was found in all CERM-containing genotypes (CERM, CERM/Stat5a+/−, CERM/Stat5a−/−) and ERα(+) adenocarcinoma in the Stat5a−/− genotype. The mammary epithelial cell proliferative index was increased only in CERM mice independent of Stat5a loss. No differences in apoptotic indices were found. In summary, Stat5a cooperated with deregulated ERα in retarding pubertal mammary differentiation and contributed to ERα-initiated preneoplasia, but its loss did not prevent development of invasive cancer. Moreover, in the absence of deregulated ERα, Stat5a loss was associated with development of both HANs and invasive cancer following DMBA exposure.

Journal Article.  5639 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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