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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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Regulation and different patterns of alternative splicing. (a) Alternative pre-mRNA splicing involves a complex interplay of trans-acting splicing factors with numerous cis-acting regulatory elements within the precursor mRNA sequences of eukaryotic genes. Trans-acting factors recognise and interact with different cis-acting RNA motifs present within the pre-mRNA sequence of genes; these include 5' donor and 3' acceptor sites at exon-intron boundaries; exon and intron enhancer elements (ESE, ISE), which can promote the use of specific splice sites; and exon and intron silencer elements (ESS, ISS), which when bound by proteins can repress the use of specific splice sites (adapted from [59]). (b) Different patterns of alternative splicing include: (i) normal pattern of splicing – removing introns 1, 2 and 3; (ii) whole exon exclusion – introns 1, 2 and 3, and entire exon 2 are removed; (iii) mutually exclusive exons – either exon 2 or exon 3 is removed and both exons are never retained together; (iv) intron retention – intron 2 is retained in the mRNA; and (v) cryptic splice sites – exon 2 contains a 3' cryptic splice site and exon 3 contains a 5' cryptic splice site. These compete with the native splice site to generate mRNA lacking part of an exon.
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Figure 2: Regulation and different patterns of alternative splicing. (a) Alternative pre-mRNA splicing involves a complex interplay of trans-acting splicing factors with numerous cis-acting regulatory elements within the precursor mRNA sequences of eukaryotic genes. Trans-acting factors recognise and interact with different cis-acting RNA motifs present within the pre-mRNA sequence of genes; these include 5' donor and 3' acceptor sites at exon-intron boundaries; exon and intron enhancer elements (ESE, ISE), which can promote the use of specific splice sites; and exon and intron silencer elements (ESS, ISS), which when bound by proteins can repress the use of specific splice sites (adapted from [59]). (b) Different patterns of alternative splicing include: (i) normal pattern of splicing – removing introns 1, 2 and 3; (ii) whole exon exclusion – introns 1, 2 and 3, and entire exon 2 are removed; (iii) mutually exclusive exons – either exon 2 or exon 3 is removed and both exons are never retained together; (iv) intron retention – intron 2 is retained in the mRNA; and (v) cryptic splice sites – exon 2 contains a 3' cryptic splice site and exon 3 contains a 5' cryptic splice site. These compete with the native splice site to generate mRNA lacking part of an exon.

Mentions: Alternative pre-mRNA splicing is a vital mechanism for generating protein diversity from a relatively small number of genes. In excess of 60% of all human genes undergo alternative splicing. Splicing occurs at sites determined by the presence of a 5' donor splice sequence (usually ending -GU), a branch point adenosine and a 3' acceptor splice sequence (usually ending -AG) within pre-mRNA sequences [32,33]. The proximity of cis-regulatory sequences, either enhancers or silencers of exon or intron splicing, influences the binding of different trans-splicing factors to the splice sites (Figure 2a) and aids assembly of the spliceosome multi-protein complex, resulting in cleavage and ligation of introns and exons, respectively [32,33]. At least five basic types of alternative splicing have been described [32-34] (Figure 2b).


Alternative splicing and the progesterone receptor in breast cancer.

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

Regulation and different patterns of alternative splicing. (a) Alternative pre-mRNA splicing involves a complex interplay of trans-acting splicing factors with numerous cis-acting regulatory elements within the precursor mRNA sequences of eukaryotic genes. Trans-acting factors recognise and interact with different cis-acting RNA motifs present within the pre-mRNA sequence of genes; these include 5' donor and 3' acceptor sites at exon-intron boundaries; exon and intron enhancer elements (ESE, ISE), which can promote the use of specific splice sites; and exon and intron silencer elements (ESS, ISS), which when bound by proteins can repress the use of specific splice sites (adapted from [59]). (b) Different patterns of alternative splicing include: (i) normal pattern of splicing – removing introns 1, 2 and 3; (ii) whole exon exclusion – introns 1, 2 and 3, and entire exon 2 are removed; (iii) mutually exclusive exons – either exon 2 or exon 3 is removed and both exons are never retained together; (iv) intron retention – intron 2 is retained in the mRNA; and (v) cryptic splice sites – exon 2 contains a 3' cryptic splice site and exon 3 contains a 5' cryptic splice site. These compete with the native splice site to generate mRNA lacking part of an exon.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2481493&req=5

Figure 2: Regulation and different patterns of alternative splicing. (a) Alternative pre-mRNA splicing involves a complex interplay of trans-acting splicing factors with numerous cis-acting regulatory elements within the precursor mRNA sequences of eukaryotic genes. Trans-acting factors recognise and interact with different cis-acting RNA motifs present within the pre-mRNA sequence of genes; these include 5' donor and 3' acceptor sites at exon-intron boundaries; exon and intron enhancer elements (ESE, ISE), which can promote the use of specific splice sites; and exon and intron silencer elements (ESS, ISS), which when bound by proteins can repress the use of specific splice sites (adapted from [59]). (b) Different patterns of alternative splicing include: (i) normal pattern of splicing – removing introns 1, 2 and 3; (ii) whole exon exclusion – introns 1, 2 and 3, and entire exon 2 are removed; (iii) mutually exclusive exons – either exon 2 or exon 3 is removed and both exons are never retained together; (iv) intron retention – intron 2 is retained in the mRNA; and (v) cryptic splice sites – exon 2 contains a 3' cryptic splice site and exon 3 contains a 5' cryptic splice site. These compete with the native splice site to generate mRNA lacking part of an exon.
Mentions: Alternative pre-mRNA splicing is a vital mechanism for generating protein diversity from a relatively small number of genes. In excess of 60% of all human genes undergo alternative splicing. Splicing occurs at sites determined by the presence of a 5' donor splice sequence (usually ending -GU), a branch point adenosine and a 3' acceptor splice sequence (usually ending -AG) within pre-mRNA sequences [32,33]. The proximity of cis-regulatory sequences, either enhancers or silencers of exon or intron splicing, influences the binding of different trans-splicing factors to the splice sites (Figure 2a) and aids assembly of the spliceosome multi-protein complex, resulting in cleavage and ligation of introns and exons, respectively [32,33]. At least five basic types of alternative splicing have been described [32-34] (Figure 2b).

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