Distinct Function of Estrogen Receptor α in Smooth Muscle and Fibroblast Cells in Prostate Development

Vitkus, Spencer; Yeh, Chiuan Ren; Lin, Hsiu Hsia; Hsu, Iawen; Yu, Jiang-Zhou; Chen, Ming; Yeh, Shuyuan

doi:10.1210/me.2012-1212

Cited by 14 publications

(9 citation statements)

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“…Early reports showed that ERα in stromal cells could affect the prostate development [ 25 , 26 ]. Another report showed that E2 plus testosterone treatment could stimulate the PCa initiation [ 27 ], however, the role of stromal ERα in the later stages of PCa progression and how it may affect immune cell infiltration and PCa metastasis is not well studied.…”

Section: Resultsmentioning

confidence: 99%

“…In prostate development, using Cre-loxP gene knockout strategy, reports have shown that ERα plays different roles in prostate epithelial as well as different types of prostate stromal cells [ 26 , 49 ]. In the PCa mouse models, both ERα knockout [ 50 ] and ERα agonist treatment [ 51 ] showed mice with activated ERα can develop high-grade PIN, suggesting ERα might play important roles in PCa progression.…”

Section: Discussionmentioning

confidence: 99%

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Estrogen receptor α in cancer associated fibroblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and macrophage infiltration in the tumor microenvironment

et al. 2016

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BackgroundCancer associated fibroblasts (CAF) play important roles in tumor growth that involves inflammation and epithelial cell differentiation. Early studies suggested that estrogen receptor alpha (ERα) was expressed in stromal cells in normal prostates and prostate cancer (PCa), but the detailed functions of stromal ERα in the PCa remain to be further elucidated.MethodsMigration and invasion assays demonstrated the presence of high levels of ERα in CAF cells (CAF.ERα(+)) suppressed PCa invasion via influencing the infiltration of tumor associated macrophages. ERα decreased CAF CCL5 secretion via suppressing the CCL5 promoter activity was examined by luciferase assay. ERα decreased CCL5 and IL-6 expression in conditioned media that was collected from CAF cell only or CAF cell co-cultured with macrophages as measured by ELISA assay.ResultsBoth in vitro and in vivo studies demonstrated CAF.ERα(+) led to a reduced macrophage migration toward PCa via inhibiting CAF cells secreted chemokine CCL5. This CAF.ERα(+) suppressed macrophage infiltration affected the neighboring PCa cells invasion and the reduced invasiveness of PCa cells are at least partly due to reduced IL6 expression in the macrophages and CAF.ConclusionOur data suggest that CAF ERα could be applied as a prognostic marker to predict cancer progression, and targeting CCL5 and IL6 may be applied as an alternative therapeutic approach to reduce M2 type macrophages and PCa invasion in PCa patients with low or little ERα expression in CAF cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0488-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Estrogen receptor α in cancer associated fibroblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and macrophage infiltration in the tumor microenvironment

et al. 2016

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“…To investigate the in vivo role of ERα in BCa development, we employed cre-loxP strategy to knock out the floxed ERα gene (ERαKO) [ 34 - 36 ]. The breeding scheme for the generation of CMV-ERαKO (Fig.…”

Section: Resultsmentioning

confidence: 99%

Estrogen Receptor Alpha Prevents Bladder Cancer Development via INPP4B inhibited Akt Pathway in vitro and in vivo

et al. 2014

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Clinical reports show males have a higher bladder cancer (BCa) incidence than females. The sexual difference of BCa occurrence suggests that estrogen and its receptors may affect BCa development. Estrogen receptor alpha (ERα) is the classic receptor to convey estrogen signaling, however, the function of ERα in BCa development remains largely unknown. To understand the in vivo role of ERα in BCa development, we generated total and urothelial specific ERα knockout mice (ERαKO) and used the pre-carcinogen BBN to induce BCa. Earlier reports showed that ERα promotes breast and ovarian cancers in females. Surprisingly and of clinical importance, our results showed that ERα inhibits BCa development and loss of the ERα gene results in an earlier onset and higher incidence of BBN-induced in vivo mouse BCa. Supportively, carcinogen induced malignant transformation ability was reduced in ERα expressing urothelial cells as compared to ERα negative cells. Mechanism studies suggest that ERα could control the expression of INPP4B to reduce AKT activity and consequently reduce BCa cell growth. In addition, IHC staining of clinical sample analyses show that INPP4B expression, in correlation with reduced ERα, is significantly reduced in human BCa specimens. Together, this is the first report using the in vivo cre-loxP gene knockout mouse model to characterize ERα roles in BCa development. Our studies provide multiple in vitro cell studies and in vivo animal model data as well as human BCa tissue analyses to prove ERα plays a protective role in BCa initiation and growth at least partly via modulating the INPP4B/Akt pathway.

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“…This interaction is mediate by ERα, which is a receptor that acts in the muscle cells and fibroblasts, and influences the proliferation of epithelial cells (Vitkus et al . ). Our data showed an increase in ERα immunoreactivity in stromal cells and the cytoplasm of epithelial cells in the prostates from male and female senile gerbils that were exposed to EE.…”

Section: Discussionmentioning

confidence: 97%

Prenatal exposure to ethinylestradiol alters the morphologic patterns and increases the predisposition for prostatic lesions in male and female gerbils during ageing

Perez

Biancardi

Caires

et al. 2016

Int J Experimental Path

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SUMMARYEthinylestradiol (EE) is an endocrine disruptor (ED) which acts as an oestrogen agonist; this compound is known as an oral contraceptive. Male and female rodents exposed to EE during critical time points of development, such as in the prenatal period, show alterations in their reproductive tract during adulthood. Few studies have placed an emphasis on the effects of EE during ageing. Thus, this study had as it's objective the analysis of the morphological and immunohistochemical effects of exposure to EE in the prenatal period on ventral male prostate and female prostate of gerbils (Meriones unguiculatus) during ageing. The animals were exposed to EE (15 lg/ kg/day) during the 18-22th days of prenatal life (EE/PRE group), and the analyses were performed when the male and female reached 12 months of age. Our results showed an increase in the development of prostatic intraepithelial neoplasia (PIN), which was observed in the male and female prostate of EE/PRE groups. Immunohistochemistry showed a rise in prostatic epithelial and basal cells immunoreactivity, respectively, and to AR and p63 in the male EE/PRE. There were alterations in the morphological pattern of the prostatic glands and increase in predisposition to emergence of prostatic lesions of both sexes during ageing. Despite male and female having been exposed to the same doses of EE, the "exposure to EE promoted modifications" more accentuated in the male prostate. Thus the male gland is more sensitive to the action of this synthetic oestrogen than the female prostate.

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Distinct Function of Estrogen Receptor α in Smooth Muscle and Fibroblast Cells in Prostate Development

Cited by 14 publications

References 57 publications

Estrogen receptor α in cancer associated fibroblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and macrophage infiltration in the tumor microenvironment

Estrogen receptor α in cancer associated fibroblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and macrophage infiltration in the tumor microenvironment

Estrogen Receptor Alpha Prevents Bladder Cancer Development via INPP4B inhibited Akt Pathway in vitro and in vivo

Prenatal exposure to ethinylestradiol alters the morphologic patterns and increases the predisposition for prostatic lesions in male and female gerbils during ageing

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