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

Leygue, Etienne; Dotzlaw, Helmut; Watson, Peter H.; Murphy, Leigh C.

doi:10.1038/sj.bjc.6690366

Cited by 4 publications

(1 citation statement)

References 18 publications

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“…Exon 6 deleted PRΔ6 mRNA has been detected in normal and tumour samples from the breast [ 50 ] and has since been detected more frequently in tumour than normal breast tissue, and at a higher rate in PR- tumours than PR+ [ 53 ]. PRΔ6 mRNA has also been detected in tissue samples from vascular smooth muscle [ 52 ], normal ovaries, ovarian endometriosis and normal endometrium [ 51 ].…”

Section: Other Progesterone Receptor Spliced Variantsmentioning

confidence: 99%

Alternative splicing and the progesterone receptor in breast cancer

2008

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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. After menarche, the cyclical release of the steroid hormones oestrogen and progesterone stimulates the primitive ducts of the immature breast to differentiate into terminal end buds, which branch into alveolar buds. During pregnancy, high circulating steroid hormone levels stimulate increased lobular differentiation to the mature secretory gland. Upon withdrawal of sex steroid hormones at menopause, involution to an undifferentiated morphology occurs [2]. IntroductionNormal mammary ducts consist of a layer of luminal epithelial cells, surrounded by a layer of myoepithelial cells, encased in delimiting fibroblasts set in a fatty, collagenous stroma [3]. Most breast carcinomas are of epithelial origin and are either localised to the duct/lobule of origin or capable of invading surrounding stroma [4]. Whilst age is the biggest contributory risk factor for developing breast cancer, use of hormone replacement therapy (HRT) and oral contraceptives have also been implicated, implicating hormone signalling in breast cancer development [1,4]. A further increased risk with combined oestrogen-progesterone HRT compared to oestrogen alone also bears out the significant role of progesterone signalling through progesterone receptor (PR) in breast cancer development [5][6][7]. PR, along with oestrogen receptor (ER), status is routinely measured in breast cancer specimens. PR+ patients are more likely to respond to hormonal therapies and survive disease [8]. Approximately 40% of breast tumours are ER+/PR+ and these patients are considered to have the best prognosis and are most likely to respond to hormonal therapies [4,9]. These cancers are associated with a lower rate of cell proliferation and well differentiated tumours, leading to a better prospect of overall s...

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Section: Other Progesterone Receptor Spliced Variantsmentioning

confidence: 99%

Alternative splicing and the progesterone receptor in breast cancer

2008

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SR Protein Expression and CD44 Splicing Pattern in Human Breast Tumours

Pind

Watson

2003

Breast Cancer Res Treat

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Altered gene expression during breast tumour progression can occur through alternative splicing of mRNAs. The SR proteins have been identified as important factors in RNA splicing and in the incorporation of alternative exons in experimental systems. We have studied SR protein expression by western blot in human breast cell lines and in a cohort of 101 invasive breast tumours to examine the relationship with alternatively spliced isoforms of the CD44 gene. Multiple SR proteins (SR75, 55, 40, 30) were expressed in most cell lines and tumours, and their relative expression was independent of grade, size, or nodal status. Higher relative expression of SR55 protein was associated with an altered pattern of CD44 variants incorporating exon v7 (p = 0.047) as determined by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis. Nevertheless, transient transfection of MCF7 and HBL100 breast cell lines with SR55 had no direct effect on the expression of CD44 v7 variant expression. We conclude that while SR proteins may be important and necessary factors in mRNA splicing, other factors are also necessary to influence the regulation of alternatively spliced isoforms of CD44.

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Variant progesterone receptor mRNAs are co-expressed with the wild-type progesterone receptor mRNA in human endometrium during all phases of the menstrual cycle

Marshburn

Zhang²,

Mostafavi³

et al. 2005

MHR: Basic Science of Reproductive Medicine

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Progesterone receptor (PR) variant mRNAs in human endometrium could encode proteins with the potential to alter progesterone action in states of normal and abnormal endometrial development. We have assessed the expression levels of mRNA for the wild-type PR and splice variants of PR mRNA lacking exon 4 (del-4 PR), exon 6 (del-6 PR), exons 4 and 6 (del-4&6 PR), and part of exon 4 (del-p4 PR) or part of exon 6 (del-p6 PR) in the human endometrium throughout menstrual cycle development. Eighty-eight endometrial specimens (47 proliferative, 41 secretory) were collected from patients undergoing hysterectomy for benign gynaecologic causes. Measurements by RT-PCR indicated that mRNAs for wild-type PR, and splice variants del-4 PR, del-6 PR, del-4&6 PR, del-p6 PR, and a novel del-p4 PR were detected in all endometrial specimens throughout the menstrual cycle. Higher levels of wild-type PR and all PR variant mRNAs were found in the early and mid-proliferative endometrial phases than in secretory endometrium. The relative expression of mRNA for all PR variants compared to wild-type PR mRNA, however, did not change through all stages of endometrial development. We, therefore, found no evidence of differential co-expression of the PR variants compared with wild-type PR during normal menstrual development. Future studies will determine if the expression profile of PR variant mRNAs will be different in the endometrium of patients with infertility, recurrent pregnancy loss, or endometrial adenocarcinoma.

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

Cited by 4 publications

References 18 publications

Alternative splicing and the progesterone receptor in breast cancer

Alternative splicing and the progesterone receptor in breast cancer

SR Protein Expression and CD44 Splicing Pattern in Human Breast Tumours

Variant progesterone receptor mRNAs are co-expressed with the wild-type progesterone receptor mRNA in human endometrium during all phases of the menstrual cycle

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