Mutational Analysis of Progesterone Receptor Functional Domains in Stable Cell Lines Delineates Sets of Genes Regulated by Different Mechanisms

Quiles, Ignacio; Millán-Ariño, Lluís; Subtil‐Rodríguez, Alicia; Miñana, Belén; Spinedi, Nora; Ballaré, Cecilia; Beato, Miguel; Jordan, Albert

doi:10.1210/me.2008-0454

Cited by 31 publications

(41 citation statements)

References 42 publications

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“…FGF2 activated both PRE-and GAS-luc. When we moved to a more physiologic setting, CCND1 and MYC mRNA were also increased by both ligands as well as all the MPA/STAT5-regulated proteins studied (30,45). The FGFR inhibitor and 2 different antiprogestins not only inhibited cell proliferation induced by MPA or FGF2, respectively, but also inhibited the induction of luciferase expression, mRNA, and protein expression.…”

Section: Discussionmentioning

confidence: 95%

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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: Discussionmentioning

confidence: 95%

“…Discussion, page 3728, second column, last paragraph: When we moved to a more physiologic setting, CCND1 and MYC mRNA were also increased by both ligands as well as all the MPA/STAT5-regulated proteins studied (45,29 To request permission to re-use all or part of this article, use this link…”

Section: Correctionmentioning

confidence: 99%

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

et al. 2011

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“…7C -iii-). The regulation of human CCND1 by progestins may be more complicated, as no canonical PRE sites have been described in its promoter and accordingly, it has been suggested that PR regulates CCND1 expression by nongenomic mechanisms (7,9,34). The 2 models of cytoplasmic signaling pathways activated by Pg are shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…7C -v-). However, it has been recently shown that PR may have genomic effects at the CCND1 promoter (34,44), even as a coactivator of STAT3 (26; Fig. 7C -iv-).…”

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor Alpha Mediates Progestin-Induced Mammary Tumor Growth by Interacting with Progesterone Receptors at the Cyclin D1/MYC Promoters

et al. 2012

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Synthetic progesterone used in contraception drugs (progestins) can promote breast cancer growth, but the mechanisms involved are unknown. Moreover, it remains unclear whether cytoplasmic interactions between the progesterone receptor (PR) and estrogen receptor alpha (ERa) are required for PR activation. In this study, we used a murine progestin-dependent tumor to investigate the role of ERa in progestin-induced tumor cell proliferation. We found that treatment with the progestin medroxyprogesterone acetate (MPA) induced the expression and activation of ERa, as well as rapid nuclear colocalization of activated ERa with PR. Treatment with the pure antiestrogen fulvestrant to block ERa disrupted the interaction of ERa and PR in vitro and induced the regression of MPA-dependent tumor growth in vivo. ERa blockade also prevented an MPA-induced increase in CYCLIN D1 (CCND1) and MYC expression. Chromatin immunoprecipitation studies showed that MPA triggered binding of ERa and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAi-mediated silencing of ERa inhibited ERa, but not PR binding to both regulatory sequences, indicating that an interaction between ERa and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ERa-PR association on target gene promoters is essential for progestin-induced cell proliferation. Cancer Res; 72(9); 2416-27. Ó2012 AACR.

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“…First, we measured the effect of BRCA1 on PR levels in the cell line FLAG-PRB-T47DYV [a PR-negative clonal derivative cell line from T47D engineered to express a FLAG-tagged form of PRB (20)]. Cell extracts were prepared from control and from cells transduced to overexpress BRCA1 (AdBRCA1; Fig.…”

Section: Brca1 Regulates the Downregulation Of Prmentioning

confidence: 99%

BRCA1 Counteracts Progesterone Action by Ubiquitination Leading to Progesterone Receptor Degradation and Epigenetic Silencing of Target Promoters

Calvo

Beato

2011

Cancer Research

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Germ-line mutations in the BRCA1 gene increase the risk of breast cancer in women, but the precise mechanistic basis for this connection remains uncertain. One popular hypothesis to explain breast tissue specificity postulates a link between BRCA1 and the action of the ovarian hormones estrogen and progesterone. Given the relevance of progesterone for normal mammary development and breast cancer formation, we searched for a functional relationship between BRCA1 and progesterone receptor (PR) in the PR-positive breast cancer cell line T47D. Here, we report that BRCA1 inhibits the transcriptional activity of PR by at least 2 mechanisms involving the E3 ubiquitin ligase activity of BRCA1. First, BRCA1 has a direct effect on the cellular level of PR and, hence, on the extent of PR recruitment to target promoters through the promotion of its ligandindependent and -dependent degradation. Through in vitro and in vivo assays, we found that BRCA1/BARD1 may be the main E3 ubiquitin ligase responsible for ubiquitination and degradation of PR in the absence of hormone. Second, after hormone treatment of cells, the BRCA1/BARD1 complex is recruited via interaction with PR to the hormone-responsive regions of PR target genes, affecting local levels of monoubiquitinated histone H2A and contributing to epigenetic silencing of these promoters. The connections between BRCA1/BARD1 and PR activity suggested by our findings may help explain why host mutations in BRCA1 exert a tissue specificity in preferentially elevating the risk of breast cancer. Cancer Res; 71(9); 3422-31. Ó2011 AACR.

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Mutational Analysis of Progesterone Receptor Functional Domains in Stable Cell Lines Delineates Sets of Genes Regulated by Different Mechanisms

Cited by 31 publications

References 42 publications

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

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

Estrogen Receptor Alpha Mediates Progestin-Induced Mammary Tumor Growth by Interacting with Progesterone Receptors at the Cyclin D1/MYC Promoters

BRCA1 Counteracts Progesterone Action by Ubiquitination Leading to Progesterone Receptor Degradation and Epigenetic Silencing of Target Promoters

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