Progesterone receptor variants found in breast cells repress transcription by wild-type receptors

Richer, Jennifer K.; Lange, Carol A.; Wierman, Ann; Brooks, Kelly; Tung, Lin; Takimoto, Glenn S.; Horwitz, Kathryn B.

doi:10.1023/a:1005941117247

Cited by 49 publications

(36 citation statements)

References 32 publications

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“…The heterogeneous expression of ER and PR receptors in our study may reflect receptor mutations with antigen loss and heterogeneous tumour populations (Richer et al, 1998). The number of patients in our study is too low to speculate about any association regarding clinical behaviour and receptor status.…”

Section: Discussionmentioning

confidence: 70%

Expression of oestrogen and progesterone receptors in low-grade endometrial stromal sarcomas

et al. 2000

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We analysed oestrogen receptor (ER) and progesterone receptor (PR) expression in a retrospective series of 21 low-grade endometrial stromal sarcomas (LGSSs). Archival formalin-fixed and paraffin-embedded material was analysed by immunohistochemistry. ER and PR were measured with monoclonal antibodies and the peroxidase-antiperoxidase method and a score was calculated as for breast carcinoma based on both the percentage of positive tumour cell nuclei and the staining intensity. ER were seen in 15 (71%) and PR in 20 (95%) of tumours respectively. ER expression was scored as high in three (14%), moderate in four (19%), and low in eight (38%) tumours. Six (29%) tumours did not stain for ER and all of these were positive for PR. PR expression was scored as high in eight (38%), moderate in ten (47%) and weak in two (10%) LGSSs. Only one (5%) LGSS did not stain for PR (this tumour was positive for ER). ER and PR expression in LGSS is heterogeneous. This may have implications for hormone therapy in the management of these tumours. These results suggest that ER and PR should be routinely quantified in LGSSs by immunohistochemical methods. © 2000 Cancer Research Campaign

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Section: Discussionmentioning

confidence: 70%

Expression of oestrogen and progesterone receptors in low-grade endometrial stromal sarcomas

et al. 2000

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“…Precooled 5% polyacrylamide gels were loaded and run at 4 °C in TGE buffer. In controls, PR-B/PRE complexes were incubated in the presence of PR-specific antibodies and were competed with unlabled PRE or SP1-site containing oligonucleotides (22).…”

Section: Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

et al. 2007

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Progesterone receptor (PR) action is linked to epidermal growth factor (EGF) initiated signaling pathways at multiple levels; mitogen-activated protein kinases (MAPKs) are key mediators of this important cross-talk. Herein, we probed the effects of EGF on PR function and regulation of breast cancer cell growth. EGF stimulated rapid and transient phosphorylation of PR-B Ser294 relative to persistent phosphorylation of this site induced by the synthetic progestin, R5020. EGF induced nuclear translocation and DNA binding of unliganded wild-type, but not mutant PRs containing an Ala at position 294 (S294A). However, EGF alone induced little to no PR-B transcriptional activity; S294A PR-B was transcriptionally impaired. In contrast, pretreatment of cells with EGF (30 min) significantly increased the potency and efficacy of wild-type, but not S294A PR transcriptional activity in response to progestin, and enhanced ligand-dependent downregulation of wild-type but not S294A PR. Replacement of Ser294 with aspartic acid (S294D) to mimic phosphorylation at this site decreased receptor stability and, as predicted, heightened progestin-induced transcription relative to wild-type PR-B. RT-PCR demonstrated the Ser294 phosphorylation-dependence of selected PR target genes (TGFα and HB-EGF). Surprisingly, PR-B expressing cells growing in soft agar were highly responsive to EGF or progestin, and this was further stimulated by the combination of both hormones. Cells expressing S294A PR exhibited reduced soft agar growth, and were also sensitive to R5020 alone, but failed to respond to EGF. These results suggest that PR Ser294 is an important "sensor" for growth factor inputs that affects PR function and breast cancer cell growth in the absence of progestin or in the presence of low or "sub-threshold" progestin concentrations. PR function likely contributes to breast cancer progression when EGFR family members or their ligands are overexpressed, a condition that predicts low abundance, but highly active and nuclear PR.

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“…The recombinant D6-PR protein, has recently been shown to bind constitutively the progesterone receptor element (PRE) DNA consensus sequence and to exhibit dominant-negative activity on PR-A-and PR-B-induced transcription (Richer et al, 1998). Interestingly, a naturally occurring ER variant mRNA deleted in exon 7 and encoding an analogous truncated molecule lacking the hormone binding domain of the WT-ER can also act as a dominant-negative regulator of WT-ER, at least under some circumstances (Wang and Miksicek, 1991;Fuqua et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Altered expression of exon 6 deleted progesterone receptor variant mRNA between normal human breast and breast tumour tissues

et al. 1999

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The progesterone receptor (PR) is an important prognostic marker in breast cancer as well as a marker of responsiveness to endocrine therapies. The presence of several exon-deleted PR variant mRNAs in both normal and neoplastic breast samples has recently been reported. Amongst them, a variant mRNA deleted in exon 6 (D6-PR mRNA) that if translated would encode a truncated PR-like protein missing the hormone binding domain and one of the transactivating domains of the wild-type PR protein. In order to determine whether changes in D6-PR variant expression could occur during tumorigenesis, its expression was investigated by reverse transcription and polymerase chain reaction in ten normal reduction mammoplasty samples, nine breast tumours with high PR levels (> 100 fmol mg −1 protein) and eight breast tumours with low PR levels (< 15 fmol mg −1 protein), as determined by ligand binding assay. The relative expression of D6-PR to wild-type PR mRNA was lower ( P < 0.01) in normal than in all tumour breast samples. Moreover, a trend to lower ( P < 0.1) relative D6-PR expression was observed in high PR tumours, compared to low PR tumours. These data suggest that increased expression of D6-PR occurs during tumorigenesis. © 1999 Cancer Research Campaign

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Progesterone receptor variants found in breast cells repress transcription by wild-type receptors

Cited by 49 publications

References 32 publications

Expression of oestrogen and progesterone receptors in low-grade endometrial stromal sarcomas

Expression of oestrogen and progesterone receptors in low-grade endometrial stromal sarcomas

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

Altered expression of exon 6 deleted progesterone receptor variant mRNA between normal human breast and breast tumour tissues

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