Cellular expression of estrogen and progesterone receptors in mammary glands: regulation by hormones, development and aging

Shyamala, G.; Chou, Yu Chien; Louie, Sharianne G.; Guzman, Raphaël; Smith, Gilbert H.; Nandi, Satyabrata

doi:10.1016/s0960-0760(01)00182-0

Cited by 114 publications

(95 citation statements)

References 49 publications

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“…The majority (60%) of naturally occurring mammary tumors examined here expressed estrogen receptors (ER) and progesterone receptors (PR); the role of estrogens and progestins in mammary carcinogenesis and growth is well established (25). In this rat model, however, social isolation was associated with senescent ovaries at the age of tumorigenesis and growth; few isolated rats had hormonally active follicles or corpora lutea, (23), confirmed here by the condition of their vaginal epithelia.…”

Section: Discussionmentioning

confidence: 55%

Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors

Hermes¹,

Delgado²,

Tretiakova³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

178

140

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In a life span study, we examined how the social environment regulates naturally occurring tumor development and malignancy in genetically prone Sprague-Dawley rats. We randomly assigned this gregarious species to live either alone or in groups of five female rats. Mammary tumor burden among social isolates increased to 84 times that of age-matched controls, as did malignancy, specifically a 3.3 relative risk for ductal carcinoma in situ and invasive ductal carcinoma, the most common early breast cancers in women. Importantly, isolation did not extend ovarian function in late middle age; in fact, isolated animals were exposed to lower levels of estrogen and progesterone in the middle-age period of mammary tumor growth, with unchanged tumor estrogen and progesterone receptor status. Isolates, however, did develop significant dysregulation of corticosterone responses to everyday stressors manifest in young adulthood, months before tumor development, and persisting into old age. Among isolates, corticosterone response to an acute stressor was enhanced and recovery was markedly delayed, each associated with increased mammary tumor progression. In addition to being stressed and tumor prone, an array of behavioral measures demonstrated that socially isolated females possessed an anxious, fearful, and vigilant phenotype. Our model provides a framework for studying the interaction of social neglect with genetic risk to identify mechanisms whereby psychosocial stressors increase growth and malignancy of breast cancer.breast cancer ͉ glucocorticoids ͉ physiological stress ͉ psychological stress ͉ social behavior

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Section: Discussionmentioning

confidence: 55%

Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors

Hermes¹,

Delgado²,

Tretiakova³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

178

140

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“…Tissue transplantation studies of epithelium and stroma between ER -null mice and wild-type mice demonstrated that estrogen responsiveness is mediated by paracrine factors, and that the ER response differs with developmental stage. In neonatal mice, ER is expressed solely in the mammary stroma (Shyamala et al 2002) and stromal ER is necessary and sufficient to induce ductal growth (Cunha et al 1997, Bocchinfuso et al 2000. In adult mice ER is expressed in a proportion of mammary epithelial and stromal cells (Shyamala et al 2002), and ER in epithelial cells appears important for tissue response to estrogens (Mueller et al 2002).…”

Section: Discussionmentioning

confidence: 99%

“…In neonatal mice, ER is expressed solely in the mammary stroma (Shyamala et al 2002) and stromal ER is necessary and sufficient to induce ductal growth (Cunha et al 1997, Bocchinfuso et al 2000. In adult mice ER is expressed in a proportion of mammary epithelial and stromal cells (Shyamala et al 2002), and ER in epithelial cells appears important for tissue response to estrogens (Mueller et al 2002). In both bovine and human mammary gland, paracrine mediation of estrogenic effects seemingly emanate from the limited number of ER -positive epithelial cells (Capuco et al 2002a, Anderson & Clarke 2004.…”

Section: Discussionmentioning

confidence: 99%

Chromosomal mapping and quantitative analysis of estrogen-related receptor alpha-1, estrogen receptors alpha and beta and progesterone receptor in the bovine mammary gland

Connor¹,

Wood²,

Sonstegard³

et al. 2005

Journal of Endocrinology

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Steroid receptors are key transcriptional regulators of mammary growth, development and lactation. Expression of estrogen receptors alpha (ER ) and beta (ER ), progesterone receptor (PR), and estrogen-related receptor alpha-1 (ERR ) have been evaluated in bovine mammary gland. The ERR is an orphan receptor that, in other species and tissues, appears to function in the regulation of estrogen-response genes including lactoferrin and medium chain acyl-CoA dehydrogenase and in mitochondrial biogenesis. Expression of ER , ER , PR and ERR was characterized in mammary tissue obtained from multiple stages of bovine mammary gland development using quantitative real-time RT-PCR. Expression was evaluated in prepubertal heifers, primigravid cows, lactating non-pregnant cows, lactating pregnant cows and nonlactating pregnant cows (n=4 to 9 animals/stage). In addition, ER , ER , PR and ERR were mapped to chromosomes 9, 10, 15 and 29 respectively, by linkage and radiation hybrid mapping. Results indicated that expression of ER , PR and ERR was largely coordinately regulated and they were present in significant quantity during all physiological stages evaluated. In contrast, ER transcripts were present at a very low concentration during all stages. Furthermore, no ER protein could be detected in bovine mammary tissue by immunohistochemistry. The ER and PR proteins were detected during all physiological states, including lactation. Our results demonstrate the presence of ER , PR and ERR during all physiological stages, and suggest a functional role for ERR and a relative lack of a role for ER in bovine mammary gland development and lactation.

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“…Classical endocrine ablation͞hormone replacement studies have demonstrated that ovarian estradiol (E 2 ) is critical for the two major phases of mammary development, ductal elongation during puberty, and lobuloalveolar development during pregnancy (1)(2)(3). E 2 acts directly on the mammary gland to stimulate ductal morphogenesis during puberty, whereas progesterone is the major stimulator of mammary epithelial DNA synthesis and alveolar development (1,4).…”

mentioning

confidence: 99%

“…In both rodent and human mammary glands, the dominant ER in the stroma is ER␤, not ER␣ (3,4,7,27,28), indicating that E 2 -stimulated growth factor release from the stroma is very likely ER␤-mediated. This finding is surprising for two reasons: (i) the overwhelming evidence that ER␣ is the receptor controlling E 2 -mediated proliferation, and (ii) the apparently normal development of the mammary gland in ER␤ Ϫ͞Ϫ mice.…”

mentioning

confidence: 99%

Estrogen receptors ERα and ERβ in proliferation in the rodent mammary gland

Cheng

Zhang

Warner

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

128

111

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Most evidence supports the view that ERα is responsible for estrogen (ovarian estradiol, E 2 )-induced proliferation in the epithelial cells of the mammary gland, but despite this, proliferating epithelial cells do not express ERα. We have examined this apparent paradox by studying the role of ERα and ERβ in E 2 -induced proliferation in mammary glands (measured by BrdUrd incorporation into DNA) in mice with intact ERβ (WT mice) and those in which the ERβ gene has been inactivated (ERβ -/- mice). On treatment of ERβ -/- mice with E 2 or ovariectomized WT mice with E 2 , tamoxifen, or a specific ERβ agonist (BAG), the number of BrdUrd-labeled cells in mammary glands increased from 3.4% in controls to 28-38% in the treated mice. This indicates that both ERα and ERβ can mediate E 2 -induced proliferation independently of each other. With specific antibodies, ERβ was found in both epithelial and stromal cells, whereas ERα was strictly epithelial. Within 4 h of a single dose of E 2 , ERα was lost from the nuclei of epithelial cells. In WT mice, ERα reappeared by 24 h, but in ERβ -/- mice, return to the nucleus was delayed by 24 h. At 4 h after E 2 , neither ERα nor progesterone receptor was detectable in BrdUrd-labeled nuclei but by 48 h after E 2 , 29% of the BrdUrd-labeled cells expressed ERα, and 21-38% expressed progesterone receptor. During 3 weeks of continuous E 2 treatment, ERβ remained in the nucleus, but there was no detectable ERα. With tamoxifen treatment, ERα remained in the nucleus, but ERβ was lost. From these results, we conclude that ERα receives the proliferation signal from E 2 , initiates DNA synthesis, and is then lost from cells. The subsequent steps in proliferation can proceed in the absence of either ERα or ERβ. ERβ facilitates the return of ERα to the nucleus and restores responsiveness to E 2 . By down-regulating ERβ, tamoxifen may prolong refractoriness to E 2 in mammary epithelium.

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Cellular expression of estrogen and progesterone receptors in mammary glands: regulation by hormones, development and aging

Cited by 114 publications

References 49 publications

Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors

Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors

Chromosomal mapping and quantitative analysis of estrogen-related receptor alpha-1, estrogen receptors alpha and beta and progesterone receptor in the bovine mammary gland

Estrogen receptors ERα and ERβ in proliferation in the rodent mammary gland

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