Mouse estrogen receptor gene knock out: Molecular characterization and resulting phenotypes

Korach, Kenneth S.; Curtis, Sylvia W.; Washburn, Todd F.; Lubahn, Dennis B.; Snedeker, Suzanne M.

doi:10.1016/0928-4680(94)90160-0

Cited by 133 publications

(170 citation statements)

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“…It was shown that targeted disruption of ERa impaired mammary gland development (Korach et al, 1996), while removal of ovaries decreased mammary alveolarization and branching morphogenesis (Bachelier et al, 2005). Consistent with higher levels of estrogen receptor and its downstream genes, the mammary gland of BRCA1-mutant mice displayed significantly more extensive branching and alveolarization, as well as increased BrdU incorporation.…”

Section: Discussionmentioning

confidence: 95%

A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation

Xiao

et al. 2007

Oncogene

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Estrogen and its receptor alpha (ERa) have been implicated in the tissue-specific tumorigenesis associated with BRCA1 mutations. However, the majority of breast cancers developed in human BRCA1 mutation carriers are ERa-negative, challenging the link between BRCA1 and estrogen/ERa in breast cancer formation. Using a mouse model lacking the full-length form of BRCA1, here we show that ERa is highly expressed in the premalignant mammary gland and initiation stages of tumorigenesis, although its expression is gradually diminished during mammary tumor progression. We demonstrate that the absence of full-length BRCA1 increases sensitivity of cells to estrogen-induced extracellular signal-regulated kinase 1/2 phosphorylation and cyclin D1 expression. The absence of BRCA1 turns the proliferation of ERa-positive cells from a paracrine fashion to an autocrine or endocrine fashion. Consequently, BRCA1-mutant cells are sensitized to estrogen-induced cell proliferation in vitro and mammary tumorigenesis in vivo. These findings illustrate a molecular mechanism for estrogen/ERa signals in BRCA1-associated tissue-specific tumor formation, and identify several key elements in the estrogen/ERasignaling cascade that can serve as potential therapeutic targets for BRCA1-associated tumorigenesis.

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Section: Discussionmentioning

confidence: 95%

A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation

Xiao

et al. 2007

Oncogene

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“…More recent data from two sources suggest that estradiol is not necessary for this permissive effect. Animals with knockout of their estrogen receptor and women with aromatase deficiency have enlarged ovaries in response to gonadotropin increments [13][14].…”

Section: Discussionmentioning

confidence: 99%

Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat

Sinha

Kaseta

Santner

et al. 1998

Breast Cancer Res Treat

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SummaryAromatase catalyzes the rate limiting step that converts androgens to estrogens. Postmenopausal women with hormone dependent breast cancer respond to first generation aromatase inhibitors such as aminoglutethimide with a marked suppression of circulating estradiol levels. In contrast, premenopausal women appear to be resistant to first generation aromatase inhibitors. The inability to block ovarian aromatase results from the low affinity of first generation inhibitors for the active site of the enzyme. Under these circumstances, the high substrate levels in the premenopausal ovary compete effectively with these inhibitors and do not allow binding of inhibitor to the active site of the enzyme.Second and third generation aromatase inhibitors with higher affinity for aromatase have now been developed and potentially could block ovarian aromatase. To test this possibility, we administered CGS 20267 (letrozole), a highly potent aromatase inhibitor, to cycling female rats. A dose dependent inhibition of uterine weight occurred with maximum effects produced by the 5 mg/kg/day dosage. During a period of 4 weeks, uterine weight was reduced to levels induced by ovariectomy. Ovarian tissue estradiol levels were inhibited by approximately 80%. As a reflection of inhibition of ovarian aromatase activity, the levels of androstenedione in the ovary increased by an order of magnitude. Both LH and FSH plasma levels increased but not to those observed after ovariectomy. The rise in gonadotropin levels induced a statistically significant but relatively small increase in ovarian weights.These results demonstrate the ability to persistently block ovarian aromatase activity in cycling rats with a potent aromatase inhibitor. This study provides a rationale for clinical trials of potent aromatase inhibitors in pre-menopausal women with breast cancer.

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“…Animals with null mutations in genes for either ER or ER show distinct skeletal abnormalities (Korach et al 1996, Lindberg et al 2001, Windahl et al 2001. Furthermore, distinct signal pathways can be activated by ER and ER (Jones et al 1999, Shapiro et al 2000, Fournier et al 2001.…”

Section: Figurementioning

confidence: 99%

Osteoblast differentiation influences androgen and estrogen receptor-alpha and -beta expression

Wiren

Evans²,

Xw³

2002

Journal of Endocrinology

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Significant levels of estrogen and androgens circulate in men and women, and both play an important role in bone metabolism. While it is well established that either estrogen or androgen replacement therapy is effective at ameliorating bone loss associated with hypogonadism, recent evidence nevertheless suggests that estrogen and androgens have distinct molecular actions on the skeleton. In this study, we have employed normal rat calvarial osteoblast cultures to characterize relative expression profiles of estrogen (ER and ER ) and androgen receptors (AR) during osteoblast differentiation. Normal osteoblast cultures can proceed through in vitro differentiation with distinct stages of proliferation, matrix maturation and mineralization in the appropriate differentiation medium containing ascorbic acid. Expression profiles of AR, ER and ER in primary cultures during osteoblast differentiation were characterized both by semi-quantitative relative RT-PCR and by Western analysis. In cultures induced to differentiate by growth in the presence of ascorbic acid, the expression profile for each receptor was unique during the course of differentiation. ER levels were elevated during matrix maturation and then declined during mineralization. ER expression was relatively constant throughout differentiation, exhibiting more constitutive expression. In contrast, AR levels were lowest during proliferation, and then increased throughout differentiation with highest levels in the most mature mineralizing cultures. Since steroid hormone action is generally mediated by specific cognate receptors, these results suggest that androgen actions may target cells during the mineralization stage of osteoblast differentiation, while estrogen action through either receptor isoform is more likely to affect osteoblasts earlier during matrix maturation. Interestingly, sex steroid receptor expression profiles did not exhibit the same patterns of regulation if osteoblast cultures were grown without ascorbic acid in medium that did not support extracellular matrix deposition. Thus, sex steroids may distinctly influence skeletal health by differential modulation of function during osteoblast differentiation.

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Mouse estrogen receptor gene knock out: Molecular characterization and resulting phenotypes

Cited by 133 publications

References 0 publications

A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation

A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation

Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat

Osteoblast differentiation influences androgen and estrogen receptor-alpha and -beta expression

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