Investigating the expression and function of the Steroid Receptor RNA Activator Protein (SRAP) in breast cancer
| dc.contributor.author | Yan, Yi | |
| dc.contributor.examiningcommittee | Murphy, Leigh (Biochemistry and Medical Genetics) Myal, Yvonne (Pathology) Xie, Jiuyong (Physiology and Pathophysiology) Rennie, Paul (University of British Columbia) | en_US |
| dc.contributor.supervisor | Leygue, Etienne (Biochemistry and Medical Genetics) | en_US |
| dc.date.accessioned | 2017-01-09T18:22:17Z | |
| dc.date.available | 2017-01-09T18:22:17Z | |
| dc.date.issued | 2009-09 | en_US |
| dc.date.issued | 2013-08 | en_US |
| dc.date.issued | 2013-10 | en_US |
| dc.date.issued | 2015-11 | en_US |
| dc.degree.discipline | Biochemistry and Medical Genetics | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Fifteen years ago, the Steroid receptor RNA activator (SRA) was identified as a functional non-coding RNA able to increase the activity of the estrogen receptor (ER), a critical player mediating the mitogenic role of estradiol in breast cancer. Interestingly, four years later, SRA appeared to be the first ever discovered functional RNA also able to encode a protein (SRAP). As such, the products of the SRA1 gene delineate a fascinating bi-faceted system involving both a functional RNA and a protein. Since its discovery, the non-coding aspect of this system has been widely investigated, with multiple groups gathering information on SRA structure and related functions. Overall, the non-coding SRA transcript is thought to act as a broad co-regulator modulating the activity of different transcription factors. Conversely, limited information has been obtained on the coding aspect (SRAP) of this system，even though SRA/SRAP is currently believed as a whole to be involved in several mechanisms including tumourigenesis, tumour progression, myogenesis and adipogenesis. In this body of work, I have attempted to define the clinical relevance of SRAP to breast cancer and extend the understanding of the cellular processes potentially regulated by this protein. I have first established that SRAP had the potential to become a new prognostic and predictive factor in specific groups of patients. Indeed, I have demonstrated, using tissue microarray analyses (TMAs), that SRAP expression was up-regulated in some breast tumours, with high levels associated with poor prognosis in Estrogen Receptor (ER) positive breast cancer patients. Using the same technique, I have further identified a positive association between a positive response to tamoxifen treatment and a high level of SRAP expression in a large cohort of ER-α negative cases. This highlights the potential for SRAP to become a new predictive factor of response to endocrine therapy in this specific group of patients. Using RNA-seq to define the transcriptomes of cervical Hela and breast MDA-MB-231 cancer cells upon depletion or overexpression of this protein, I further identified cellular movement amongst the potential cellular processes affected by changes in SRAP expression. Using classical trans-wells assays as well as an live-cell imaging assays, I have confirmed that SRAP indeed regulates individual cancer cell motility. Overall, my results provide critical new insights into the potential functions of the protein counterpart of the intriguing SRA/SRAP bi-faceted gene system. SRAP herein appears as a potential new therapeutic target in the fight against breast cancer that remains to be further investigated. | en_US |
| dc.description.note | February 2017 | en_US |
| dc.identifier.citation | Yan Y, Cooper C, Davie JR, McManus K, Murphy LC, Myal Y, Leygue E. The Steroid receptor RNA Activator protein (SRAP) controls cancer cell migration/motility. FEBS Lett. 2015 Nov12. pii: S0014-5793(15)00978-3. | en_US |
| dc.identifier.citation | Yan Y, Penner CP, Murphy LM, Leygue E. Steroid Receptor RNA Activator Protein (SRAP) expression as a prognostic factor in ER+ human Breast Tumour. J Cancer Res Clin Oncol. 2013 Oct;139(10):1637-47 | en_US |
| dc.identifier.citation | Yan Y, Li X, Bramwell VH, Myal Y, Penner C, Watson PH, Leygue E, Murphy LC. Expression of both ER-β1 and its co-regulator Steroid Receptor RNA Activator Protein (SRAP) are predictive for benefit from tamoxifen therapy in patients with Estrogen Receptor-alpha (ER-α)-Negative Early Breast Cancer (EBC). Ann Oncol. 2013 Aug;24(8):1986-93 | en_US |
| dc.identifier.citation | Yan Y, Skliris G, Murphy LM, Leygue E: Steroid Receptor RNA activator protein (SRAP) is a Putative Prognostic Maker in ER-positive, Node-negative Younger Breast Cancer Patients. Breast Cancer Res. 2009 Sep 9;11(5):R67 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/32000 | |
| dc.language.iso | eng | en_US |
| dc.publisher | Breast cancer research | en_US |
| dc.publisher | Journal of cancer research and clinical oncology | en_US |
| dc.publisher | annals of oncology | en_US |
| dc.publisher | Febs letter | en_US |
| dc.rights | open access | en_US |
| dc.subject | SRA, SRAP, Breast cancer | en_US |
| dc.title | Investigating the expression and function of the Steroid Receptor RNA Activator Protein (SRAP) in breast cancer | en_US |
| dc.type | doctoral thesis | en_US |