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Alternative splicing and the progesterone receptor in breast cancer.

Cork DM, Lennard TW, Tyson-Capper AJ - Breast Cancer Res. (2008)

Bottom Line: These variants may alter the progestin responsiveness of a tissue and contribute to the abnormal growth associated with breast cancer.Absence of specific functional domains from these spliced variants may also make them undetectable or indistinguishable from full length progesterone receptor by conventional antibodies.This, in turn, may aid the development of new biomarkers of disease prognosis and improve adjuvant treatment decisions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Surgical and Reproductive Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

ABSTRACT
Progesterone receptor status is a marker for hormone responsiveness and disease prognosis in breast cancer. Progesterone receptor negative tumours have generally been shown to have a poorer prognosis than progesterone receptor positive tumours. The observed loss of progesterone receptor could be through a range of mechanisms, including the generation of alternatively spliced progesterone receptor variants that are not detectable by current screening methods. Many progesterone receptor mRNA variants have been described with deletions of various whole, multiple or partial exons that encode differing protein functional domains. These variants may alter the progestin responsiveness of a tissue and contribute to the abnormal growth associated with breast cancer. Absence of specific functional domains from these spliced variants may also make them undetectable or indistinguishable from full length progesterone receptor by conventional antibodies. A comprehensive investigation into the expression profile and activity of progesterone receptor spliced variants in breast cancer is required to advance our understanding of tumour hormone receptor status. This, in turn, may aid the development of new biomarkers of disease prognosis and improve adjuvant treatment decisions.

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Progesterone receptor (PR) gene and main isoforms. (a) Exon organisation map of the PR gene, showing PR-A and PR-B promoters (indicated by arrows). (b) PR-B and PR-A protein structures. The A/B region is encoded by exon 1 and part of exon 2, and contains the PR-B specific transactivation domain AF-3, AF-1, common to PR-B and PR-A, and the PR-A specific inhibitory domain (ID). The C region forms the DNA binding domain (DBD); each of exons 2 and 3 encodes one zinc finger. The D region is encoded by exon 4 and part of exon 3, and forms the hinge region responsible for the nuclear location signal (NLS). The E region contains AF-2, common to PR-B and PR-A, and the hormone (ligand) binding domain (LBD), encoded by exons 4 to 8. (c) PR-C, an amino-terminally deleted PR protein predicted to result from alternative translation initiation at a methionine at position 595. PR-C lacks a complete DBD and the first two transactivation domains (AF-3 and AF-1).
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Figure 1: Progesterone receptor (PR) gene and main isoforms. (a) Exon organisation map of the PR gene, showing PR-A and PR-B promoters (indicated by arrows). (b) PR-B and PR-A protein structures. The A/B region is encoded by exon 1 and part of exon 2, and contains the PR-B specific transactivation domain AF-3, AF-1, common to PR-B and PR-A, and the PR-A specific inhibitory domain (ID). The C region forms the DNA binding domain (DBD); each of exons 2 and 3 encodes one zinc finger. The D region is encoded by exon 4 and part of exon 3, and forms the hinge region responsible for the nuclear location signal (NLS). The E region contains AF-2, common to PR-B and PR-A, and the hormone (ligand) binding domain (LBD), encoded by exons 4 to 8. (c) PR-C, an amino-terminally deleted PR protein predicted to result from alternative translation initiation at a methionine at position 595. PR-C lacks a complete DBD and the first two transactivation domains (AF-3 and AF-1).

Mentions: The human PR gene consists of eight coding exons separated by seven non-coding introns [16]. The two main nuclear isoforms, PR-A and PR-B [17-20], are independently regulated from defined promoter regions within the PR gene [18,21]. PR-A is a truncated form of PR-B, lacking the amino-terminal 164 amino acids that form the third transactivation domain (AF-3) [18,20]. Other than this, the two forms are structurally identical (Figure 1).


Alternative splicing and the progesterone receptor in breast cancer.

Cork DM, Lennard TW, Tyson-Capper AJ - Breast Cancer Res. (2008)

Progesterone receptor (PR) gene and main isoforms. (a) Exon organisation map of the PR gene, showing PR-A and PR-B promoters (indicated by arrows). (b) PR-B and PR-A protein structures. The A/B region is encoded by exon 1 and part of exon 2, and contains the PR-B specific transactivation domain AF-3, AF-1, common to PR-B and PR-A, and the PR-A specific inhibitory domain (ID). The C region forms the DNA binding domain (DBD); each of exons 2 and 3 encodes one zinc finger. The D region is encoded by exon 4 and part of exon 3, and forms the hinge region responsible for the nuclear location signal (NLS). The E region contains AF-2, common to PR-B and PR-A, and the hormone (ligand) binding domain (LBD), encoded by exons 4 to 8. (c) PR-C, an amino-terminally deleted PR protein predicted to result from alternative translation initiation at a methionine at position 595. PR-C lacks a complete DBD and the first two transactivation domains (AF-3 and AF-1).
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Related In: Results  -  Collection

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Figure 1: Progesterone receptor (PR) gene and main isoforms. (a) Exon organisation map of the PR gene, showing PR-A and PR-B promoters (indicated by arrows). (b) PR-B and PR-A protein structures. The A/B region is encoded by exon 1 and part of exon 2, and contains the PR-B specific transactivation domain AF-3, AF-1, common to PR-B and PR-A, and the PR-A specific inhibitory domain (ID). The C region forms the DNA binding domain (DBD); each of exons 2 and 3 encodes one zinc finger. The D region is encoded by exon 4 and part of exon 3, and forms the hinge region responsible for the nuclear location signal (NLS). The E region contains AF-2, common to PR-B and PR-A, and the hormone (ligand) binding domain (LBD), encoded by exons 4 to 8. (c) PR-C, an amino-terminally deleted PR protein predicted to result from alternative translation initiation at a methionine at position 595. PR-C lacks a complete DBD and the first two transactivation domains (AF-3 and AF-1).
Mentions: The human PR gene consists of eight coding exons separated by seven non-coding introns [16]. The two main nuclear isoforms, PR-A and PR-B [17-20], are independently regulated from defined promoter regions within the PR gene [18,21]. PR-A is a truncated form of PR-B, lacking the amino-terminal 164 amino acids that form the third transactivation domain (AF-3) [18,20]. Other than this, the two forms are structurally identical (Figure 1).

Bottom Line: These variants may alter the progestin responsiveness of a tissue and contribute to the abnormal growth associated with breast cancer.Absence of specific functional domains from these spliced variants may also make them undetectable or indistinguishable from full length progesterone receptor by conventional antibodies.This, in turn, may aid the development of new biomarkers of disease prognosis and improve adjuvant treatment decisions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Surgical and Reproductive Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

ABSTRACT
Progesterone receptor status is a marker for hormone responsiveness and disease prognosis in breast cancer. Progesterone receptor negative tumours have generally been shown to have a poorer prognosis than progesterone receptor positive tumours. The observed loss of progesterone receptor could be through a range of mechanisms, including the generation of alternatively spliced progesterone receptor variants that are not detectable by current screening methods. Many progesterone receptor mRNA variants have been described with deletions of various whole, multiple or partial exons that encode differing protein functional domains. These variants may alter the progestin responsiveness of a tissue and contribute to the abnormal growth associated with breast cancer. Absence of specific functional domains from these spliced variants may also make them undetectable or indistinguishable from full length progesterone receptor by conventional antibodies. A comprehensive investigation into the expression profile and activity of progesterone receptor spliced variants in breast cancer is required to advance our understanding of tumour hormone receptor status. This, in turn, may aid the development of new biomarkers of disease prognosis and improve adjuvant treatment decisions.

Show MeSH
Related in: MedlinePlus