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Languages : en
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Transforming growth factor [beta]1 (TGF[beta]1) is a potent inhibitor of mammary epithelial proliferation. In human breast, estrogen receptor [alpha] (ER[alpha]) cells rarely co-localize with markers of proliferation, but their increased frequency correlates with breast cancer risk. To determine whether TGF[beta]1 is necessary for the quiescence of ER[alpha]-positive population, we examined mouse mammary epithelial gland at estrus. Approximately 35% of cells showed TGF[beta]1 activation, which co-localized with nuclear receptor-phosphorylated Smad 2/3, indicating that TGF[beta] signaling is autocrine. Furthermore, nuclear Smad co-localized with nuclear ER[alpha]. To test whether TGF[beta] was functional, we examined genetically engineered mice with different levels of TGF[beta]1. ER[alpha] co-localization with markers of proliferation (i.e. Ki-67 or BrdU) at estrus was significantly increased in the mammary glands of Tgf[beta]1 C57/bl/129SV heterozygote mice. This relationship was maintained following pregnancy, but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF[beta]1 via the MMTV promoter suppressed proliferation of ER[alpha] positive cells. Thus, TGF[beta]1 activation functionally restrains ER[alpha] positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF[beta]1 dysregulation may promote proliferation of ER[alpha] positive cells associated with breast cancer risk in humans.
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Languages : en
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Transforming growth factor [beta]1 (TGF[beta]1) is a potent inhibitor of mammary epithelial proliferation. In human breast, estrogen receptor [alpha] (ER[alpha]) cells rarely co-localize with markers of proliferation, but their increased frequency correlates with breast cancer risk. To determine whether TGF[beta]1 is necessary for the quiescence of ER[alpha]-positive population, we examined mouse mammary epithelial gland at estrus. Approximately 35% of cells showed TGF[beta]1 activation, which co-localized with nuclear receptor-phosphorylated Smad 2/3, indicating that TGF[beta] signaling is autocrine. Furthermore, nuclear Smad co-localized with nuclear ER[alpha]. To test whether TGF[beta] was functional, we examined genetically engineered mice with different levels of TGF[beta]1. ER[alpha] co-localization with markers of proliferation (i.e. Ki-67 or BrdU) at estrus was significantly increased in the mammary glands of Tgf[beta]1 C57/bl/129SV heterozygote mice. This relationship was maintained following pregnancy, but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF[beta]1 via the MMTV promoter suppressed proliferation of ER[alpha] positive cells. Thus, TGF[beta]1 activation functionally restrains ER[alpha] positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF[beta]1 dysregulation may promote proliferation of ER[alpha] positive cells associated with breast cancer risk in humans.
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Languages : en
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The objective of our research is to examine the expression patterns of estrogen receptor (ER-alpha), progesterone receptor (PR) and C-Neu in mammary glands of wild type and C-Neu transgenic mice during various developmental states and identify the relationships between these expression patterns to cells undergoing proliferation. In previous studies, we demonstrated that there were differences between the mammary glands of wild type and C-Neu mice with regard to their expression patterns of PR. And were apparent as early as six weeks of age. Our present studies reveal that mammary glands of c-neu mice contain abnormal structures with a high rate of proliferation and also that this is ovarian steroid/estrogen independent and detectable as early as 6 weeks of age. The average onset of mammary tumors in c-neu mice is approximately 30-32 weeks Yet, our studies, so far, indicate that c-neu dependent alterations in ovarian steroid hormonal regulation of mammary epithelial cells represent early events and not a late phenomenon associated with tumor progression We propose that estrogen independent proliferation may be intrinsic to mammary cells that over express c-neu. If so, both blocking erbB2 activity and the use of appropriate SERMS may be more beneficial in the clinical management of c-neu cancers.
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Languages : en
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Our previous results have shown that the basement membrane (BM) regulated the expression and function of estrogen receptor-alpha (ERa) in mouse mammary epithelial cells. New results shown here indicate that the presence of lactogenic hormones was required for the regulatory effect of BM on ERa levels. We present evidence that cell adhesion to the BM components collagen-IV, through alpha 2 and beta 1 integrin subunits and laminin-l, through alpha 2, alpha 6 and beta 1 subunits are the relevant interactions responsible for transducing the signal of the BM that increases ERa expression. On the other hand, BM- induced changes in cell proliferation and cell morphology were not involved. Thus, the changes observed in ER expression and estrogenic effect when mammary epithelial cells are removed from the gland and placed in culture could be due to the disruption of the tissue organization and, in particular, to the lack of cell-matrix interactions on tissue culture plastic. Our system model could be useful to better understand the mechanisms involved in the regulation of ER expression and function during mammary gland development and breast tumor progression.
Author: Yuxin Feng
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Languages : en
Pages : 161
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ERá is a critical regulator in breast cancer and mammary gland development. Deregulation of ER signaling correlates with abnormal mammary gland development and breast cancer. However, the role of epithelial ER remains to be clarified in vivo and the mechanism of ER signaling regulation is far from comprehensive. We hypothesize that 1) mammary epithelial ER plays critical roles in mammary gland development during pregnancy and lactation and that 2) novel, as yet identified factors in ER transcriptional regulation are involved in breast cancer development. The loxP-Cre system was used to generate epithelial ERKO mice. The well characterized MMTV-Cre and WAP-Cre transgenic mice were used to delete ER in mammary epithelial cells at different developmental stages. Early expression of MMTV-Cre arrested mammary gland development at the neonatal stage. Successive pregnancy and lactation activated epithelial ER ablation, which compromised side-branching, alveolar development, and epithelial proliferation. Further analysis revealed a massive loss of luminal epithelial cells presumably caused by apoptosis. The abnormal mammary gland development decreased milk production, thereby, caused growth retardation in the offspring. Similar phenotypes were also observed in MMTV-ERKO females in lactation. Thus, we concluded that epithelial ER is essential for mammary gland development during pregnancy and lactation stages. To further pursue the molecular mechanism of ER signaling regulation, a human mammary gland cDNA library was screened to identify novel factors that interact with ER. One novel ERá binding protein identified in the screen contains two conserved LXXLL motifs (NR-box) and a coiled-coil domain. The protein product, which we named NRCC, consists of 3 isoforms that vary in their N-terminal region. NRCC is conserved in vertebrates and its mRNA was detected in human breast cancer cells and mouse breast tumors. We found that NRCC-A interacts with ERá and enhances ERá transcriptional activity in human cancer cells. Moreover, NRCC-A co-localized with ERá in the cell nucleus and was recruited to ER target gene promoters. SiRNA analysis indicated that NRCC proteins are important for endogenous ERá-mediated transcriptional activity and estrogen dependent cell proliferation. Taken together, these data indicate that NRCC-A is a novel coactivator for ERá.
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Languages : en
Pages : 22
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Breast tumorigenesis and breast cancer progression involves the deregulation and hyperactivation of intracellular signalling proteins that lead to uncontrolled cellular proliferation, invasion and eventually, metastasis. During breast cancer development, there is a marked upregulation of estrogen receptor-alpha (ERalpha)(l) expression levels that is accompanied by alterations in estrogen responsiveness. Within normal breast epithelium, the majority of proliferating cells are ERalpha negative(2), while in breast tumors it is the ERalpha positive cells that are associated with an increase in cellular proliferation and metastasis(3), suggesting that estrogen action changes from that of an indirect mitogen to a direct mitogen. Although the mechanism by which ER becomes deregulated during breast tumorigenesis and breast cancer progression is unknown, the fact that alterations in other factors that enhance ER activity also change during breast cancer development(4) may be an underlying factor. In addition to the ER, expression and cellular responses to the transforming growth factor-beta (TGFbeta) signalling pathway also change during breast tumorigenesis and breast cancer progression. For normal mammary epithelial cells, TGFbeta is a potent physiological inhibitor of cell cycle progression(5). In breast cancer, however, cells have lost their natural growth inhibitory response to TGFbeta and may become more aggressive and more likely to metastasize in the presence of this factor(6).
Author: Xiaozheng Song
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Languages : en
Pages : 476
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The mammary gland cell growth and differentiation are under the control of both systemic honnones and locally produced growth factors. Among all these important honnones and growth factors,· estrogen plays a central role in mammary gland development. The biological function of estrogen is mediated by estrogen receptor Alpha. (ER[Alpha].) and estrogen receptor Beta (ER[Beta]). Both ER[Alpha] and ER[Beta] are expressed in the mammary gland, but with distinct expression patterns. In the mammary gland, ER[Alpha] has been proved to be the estrogen receptor that mediates the mitogenic function of estrogen. However the function of ER[Beta] in mammary cell proliferation is less understood and there remains some controversy. Accumulating evidence indicates that ER[Beta], unlike ER[Alpha], is a negative regulator of mammary epithelial cell proliferation.
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Languages : en
Pages : 41
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It is known that the actions of estrogen in mammary development are mediated primarily by the estrogen receptor alpha (ER alpha). It is not known whether ER alpha in epithelium (the tissue in which breast cancer develops) contribute to mammary cell proliferation and ductal development, or whether ER% target genes with classical estrogen response elements (EREs) or with alternative response elements, especially AP-i and CRE elements, mediate proliferation. We have been successful in developing transgenic mice with expression of wild type and AP-1/CRE superactive human ER alpha (K206A) in mammary gland and reproductive track (vaginal-cervical) epithelium. We use d the keratin 14 gene promoter to drive expression in mammary basal epithelial cells and cervical- vaginal epithelium, and the MMTV promoter to drive expression throughout the mammary epithelium. In the K14 transgenics, expression in the genital tract was efficient and caused hypoproliferation, cyclin D1 over-expression and organ enlargement. Expression of human ERs in the mammary basal cells was less strong, but excessive proliferation and lobular development occurred after estrogen treatment in these animals. We have applied for funding from NIH to finish the study of the mammary gland in these animals and in the MMTV transgenics, which appear to have good expression of the transgene in mammary glands. We tentatively conclude that human ER alpha can function to mediate proliferation in the epithelial cells of the reproductive track and mammary gland, and that the target genes with AP-1/CRE elements are important in this process. If further studies confirm these observations it will suggest that the ER alpha pathway to AP-1/CRE target genes is a key target for interventions to prevent breast cancer.
Author: Suzy Issam El Bader
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Category : Epithelial cells
Languages : en
Pages : 108
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Author: Sonia B. Jakowlew
Publisher: Springer Science & Business Media
ISBN: 1597452939
Category : Medical
Languages : en
Pages : 785
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Transforming Growth Factor- ß in Cancer Therapy, Vols. 1 and 2, provides a compendium of findings about the role of transforming growth factor- ß (TGF- ß) in cancer treatment and therapy. The second volume, Cancer Treatment in Therapy, is divided into three parts. The companion volume details the role of TGF- ß on basic and clinical biology.
Author: Xiaoyuan Zhao
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Category :
Languages : en
Pages : 170
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