Estrogen and Progesterone are Critical Regulators of Stat5a Expression in the Mouse Mammary Gland

Santos, Sarah J.; Haslam, Sandra Z.; Conrad, Susan E.

doi:10.1210/en.2007-0594

Cited by 37 publications

(45 citation statements)

References 36 publications

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“…36, 37; (reviewed in refs. 34, 38)] and by MPA (15,(39)(40)(41), focusing on STAT5 which plays a role in mammary tum origenesis (11,13) and in progesterone-mediated effects on the normal mammary gland (16,26). We report that FGF2 and MPA induced ERK, AKT, and STAT5 activation, in agreement with a recent report showing that FGF2 activates STAT5 in endothelial cells by a SRC-and JAK2-dependent mechanism (6).…”

Section: Discussionsupporting

confidence: 89%

“…Given that (a) STAT5 is localized exclusively in PRþ ERþ mammary gland cells (26), (b) progesterone activates STAT5 (14,16), (c) FGF2 activates STAT5 in endothelial cells (9), (d) a dominant negative STAT5 inhibits T47D cell proliferation (27), and (e) FGF2 and MPA induce STAT5 phosphorylation in Bottom, quantification of the levels of activated proteins in relation to the total amount of protein of the immunoblots. ERKs were used as loading controls.…”

Section: Mpa and Fgf2 Induce Erk Akt And Stat5 Phosphorylationmentioning

confidence: 99%

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Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

et al. 2011

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Fibroblast growth factor (FGF) receptor 2 (FGFR-2) polymorphisms have been associated with an increase in estrogen receptor and progesterone receptor (PR)-positive breast cancer risk; however, a clear mechanistic association between FGFR-2 and steroid hormone receptors remains elusive. In previous works, we have shown a cross talk between FGF2 and progestins in mouse mammary carcinomas. To investigate the mechanisms underlying these interactions and to validate our findings in a human setting, we have used T47D human breast cancer cells and human cancer tissue samples. We showed that medroxyprogesterone acetate (MPA) and FGF2 induced cell proliferation and activation of ERK, AKT, and STAT5 in T47D and in murine C4-HI cells. Nuclear interaction between PR, FGFR-2, and STAT5 after MPA and FGF2 treatment was also showed by confocal microscopy and immunoprecipitation. This effect was associated with increased transcription of PRE and/or GAS reporter genes, and of PR/STAT5-regulated genes and proteins. Two antiprogestins and the FGFR inhibitor PD173074, specifically blocked the effects induced by FGF2 or MPA respectively. The presence of PR/FGFR-2/ STAT5 complexes bound to the PRE probe was corroborated by using NoShift transcription and chromatin immunoprecipitation of the MYC promoter. Additionally, we showed that T47D cells stably transfected with constitutively active FGFR-2 gave rise to invasive carcinomas when transplanted into NOD/SCID mice. Nuclear colocalization between PR and FGFR-2/STAT5 was also observed in human breast cancer tissues. This study represents the first demonstration of a nuclear interaction between FGFR-2 and STAT5, as PR coactivators at the DNA progesterone responsive elements, suggesting that FGFRs are valid therapeutic targets for human breast cancer treatment. Cancer Res; 71(10); 3720-31. Ó2011 AACR.

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Section: Discussionsupporting

confidence: 89%

Section: Mpa and Fgf2 Induce Erk Akt And Stat5 Phosphorylationmentioning

confidence: 99%

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

et al. 2011

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“…Although interactions between estrogen and Stat5 signaling have been investigated, the Stat5a gene as a target for ER has only recently been suggested in a study involving mammary tissue (36), where levels of STAT5a protein were low following ovariectomy but increased after E 2 and progesterone treatments. We noted that uterine Stat5a transcript was increased by E 2 after 2 h in the WT and that no increase was seen in either KIKO or ER␣ null uteri.…”

Section: Discussionmentioning

confidence: 99%

Estrogen-mediated Regulation of Igf1 Transcription and Uterine Growth Involves Direct Binding of Estrogen Receptor α to Estrogen-responsive Elements

Hewitt

Yin

et al. 2010

Journal of Biological Chemistry

108

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Estrogen enables uterine proliferation, which depends on synthesis of the IGF1 growth factor. This proliferation and IGF1 synthesis requires the estrogen receptor (ER), which binds directly to target DNA sequences (estrogen-responsive elements or EREs), or interacts with other transcription factors, such as AP1, to impact transcription. We observe neither uterine growth nor an increase in Igf1 transcript in a mouse with a DNA-binding mutated ER␣ (KIKO), indicating that both Igf1 regulation and uterine proliferation require the DNA binding function of the ER. We identified several potential EREs in the Igf1 gene, and chromatin immunoprecipitation analysis revealed ER␣ binding to these EREs in wild type but not KIKO chromatin. STAT5 is also reported to regulate Igf1; uterine Stat5a transcript is increased by estradiol (E 2 ), but not in KIKO or ␣ERKO uteri, indicating ER␣-and ERE-dependent regulation. ER␣ binds to a potential Stat5a ERE. We hypothesize that E 2 increases Stat5a transcript through ERE binding; that ER␣, either alone or together with STAT5, then acts to increase Igf1 transcription; and that the resulting lack of IGF1 impairs KIKO uterine growth. Treatment with exogenous IGF1, alone or in combination with E 2 , induces proliferation in wild type but not KIKO uteri, indicating that IGF1 replacement does not rescue the KIKO proliferative response. Together, these observations suggest in contrast to previous in vitro studies of IGF-1 regulation involving AP1 motifs that direct ER␣-DNA interaction is required to increase Igf1 transcription. Additionally, full ER␣ function is needed to mediate other cellular signals of the growth factor for uterine growth.

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“…Both oestrogen and progesterone play critical roles in regulating STAT5 expression in the mammary gland [62,63]. One event shown to involve prolactin signalling in HS-MECs is the potentiation of RANKL signalling, via progesterone recruitment of STAT5 to RANKL enhancer regions [64,65], thus increasing this principal mediator of alveolar progenitor expansion.…”

Section: Hormones Integrating With/influencing Erα And/or Pgr That Rementioning

confidence: 99%

Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

Tarulli

Laven-Law

Shakya

et al. 2015

J Mammary Gland Biol Neoplasia

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The hormone-sensing mammary epithelial cell (HS-MEC-expressing oestrogen receptor-alpha (ERα) and progesterone receptor (PGR)) is often represented as being terminally differentiated and lacking significant progenitor activity after puberty. Therefore while able to profoundly influence the proliferation and function of other MEC populations, HS-MECs are purported not to respond to sex hormone signals by engaging in significant cell proliferation during adulthood. This is a convenient and practical simplification that overshadows the sublime, and potentially critical, phenotypic plasticity found within the adult HS-MEC population. This concept is exemplified by the large proportion (~80 %) of human breast cancers expressing PGR and/or ERα, demonstrating that HS-MECs clearly proliferate in the context of breast cancer. Understanding how HS-MEC proliferation and differentiation is driven could be key to unraveling the mechanisms behind uncontrolled HS-MEC proliferation associated with ERα- and/or PGR-positive breast cancers. Herein we review evidence for the existence of a HS-MEC progenitor and the emerging plasticity of the HS-MEC population in general. This is followed by an analysis of hormones other than oestrogen and progesterone that are able to influence HS-MEC proliferation and differentiation: androgens, prolactin and transforming growth factor-beta1.

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Estrogen and Progesterone are Critical Regulators of Stat5a Expression in the Mouse Mammary Gland

Cited by 37 publications

References 36 publications

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

Estrogen-mediated Regulation of Igf1 Transcription and Uterine Growth Involves Direct Binding of Estrogen Receptor α to Estrogen-responsive Elements

Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

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