Functional Significance of Selective Expression of ERα and ERβ in Mammary Gland Organ Culture
Rajendra G. Mehta
Thoracic pair of mammary glands from steroid hormone-pretreated mice respond to hormones structurally and functionally in organ culture. A short exposure of glands for 24 h to 7,12 Dimethylbenz(a)anthracene (DMBA) during a 24-day culture period induced alveolar or ductal lesions. Methods: To differentiate the functional significance of ER&alpha: and ER&beta:, we employed estrogen receptor (ER) knockout mice. We compared the effects of DMBA on the development of preneoplastic lesions in the glands in the absence of ER&alpha: (&alpha:ERKO) and ER&beta: (&beta:ERKO) using an MMOC protocol. Glands were also subjected to microarray analyses. We showed that estradiol can be replaced by EGF for pretreatment of mice. The carcinogen-induced lesions developed under both steroids and EGF pretreatment protocols. The glands from &alpha:ERKO did not develop any lesions, whereas in &beta:ERKO mice in which ER&alpha: is intact, mammary alveolar lesions developed. Comparison of microarrays of control, &alpha:ERKO and &beta:ERKO mice showed that ER&alpha: was largely responsible for proliferation and the MAP kinase pathways, whereas ER&beta: regulated steroid metabolism-related genes. The results indicate that ER&alpha: is essential for the development of precancerous lesions. Both subtypes, ER&alpha: and Er&beta:, differentially regulated gene expression in mammary glands in organ cultures.
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