Research Institute in Oncology and Hematology

Leigh Murphy

Breast Cancer

Dr Leigh Murphy
Research Institute in Oncology and Hematology
6020-675 McDermot Ave
Winnipeg, Mb R3E 0V9
(204) 787-4071
Email: Dr Leigh Murphy PhD

Phosphorylation Patterns in Breast Cancer

Since estrogen is a major driver of human breast cancer, and the action of estrogen changes during breast tumourigenesis and breast cancer progression, the overall aim of my research program is to elucidate the mechanisms by which estrogen action changes during the development of breast cancer and how breast cancers develop resistance to endocrine therapies and progress from hormone dependence to independence. To do this my group is identifying the molecular players involved in the estrogen receptor signaling pathways in human breast tissues, how they are altered during tumourigenesis, and breast cancer progression to hormone independence.

I am specifically determining the types and putative function of estrogen receptor isoforms, i.e. estrogen receptor alpha and beta and phosphorylated forms of estrogen receptor alpha, that are expressed in human breast tissues in vivo, using tissues obtained from the Manitoba Breast Tumour Bank/Clinical Database. Isoforms that are altered in vivo are tested in laboratory models for the functional consequences of that alteration. Estrogen and androgen signalling may have a role in some lung cancers so in collaboration with Drs Marshall Pitz, Shantanu Banerji, Sri Navaratnam and Gefei Qing, we are developing human lung cancer tissue microarrays and associated clinical information to explore the molecular players involved in the estrogen and androgen signaling pathways in lung tissue and relationship to clinical outcome.
In collaboration with Dr Peter Watson and the Manitoba Tumour Bank, we are also investigating tissue collection issues that may affect detection of various gene products in banked tissues.

Team Members

  • Charlene Bergen (Lab Assistant)
  • Kanyarat Ung (Technician)
  • Christine Bruce (Research Associate)

Publications since 2010

PubMed Listed Publication
  1. A 10-Gene Yin Yang Expression Ratio Signature for Stage IA and IB Non-Small Cell Lung Cancer. Xu W, Jia G, Davie JR, Murphy L, Kratzke R, Banerji S. J Thorac Oncol. 2016 Aug 4. pii: S1556-0864(16)30702-X. doi: 10.1016/j.jtho.2016.07.023. [Epub ahead of print]
  2. Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of pentose phosphate pathway enzymes. Wang J, Duan Z, Nugent Z, Zou JX, Borowsky AD, Zhang Y, Tepper CG, Li JJ, Fiehn O, Xu J, Kung HJ, Murphy LC, Chen HW. Cancer Lett. 2016 Aug 10;378(2):69-79. doi: 10.1016/j.canlet.2016.05.004. Epub 2016 May 6.
  3. Parental Decision Making Regarding the Disclosure or Nondisclosure of a Mutation-Positive BRCA1/2 Test Result to Minors. Seenandan-Sookdeo KA, Hack TF, Lobchuk M, Murphy L, Marles S. Oncol Nurs Forum. 2016 May 1;43(3):330-41. doi: 10.1188/16.ONF.330-341.
  4. Regulation of steroid hormone receptors and coregulators during the cell cycle highlights potential novel function in addition to roles as transcription factors. Zheng Y, Murphy LC. Nucl Recept Signal. 2016 Jan 13;14:e001. doi: 10.1621/nrs.14001. eCollection 2016. Review.
  5. The steroid receptor RNA activator protein (SRAP) controls cancer cell migration/motility. Yan Y, Cooper C, Hamedani MK, Guppy B, Xu W, Tsuyuki D, Zhang C, Nugent Z, Blanchard A, Davie JR, McManus K, Murphy LC, Myal Y, Leygue E. FEBS Lett. 2015 Nov 17. pii: S0014-5793(15)00978-3. doi: 10.1016/j.febslet.2015.11.007. [Epub ahead of print] PubMed PMID: 26581859.
  6. Estrogen regulates luminal progenitor cell differentiation through H19 gene expression. Basak P, Chatterjee S, Weger S, Bruce MC, Murphy LC, Raouf A. Endocr Relat Cancer. 2015 Aug;22(4):505-17. doi: 10.1530/ERC-15-0105. Epub 2015 May 5.
  7. Intratumoural inflammation and endocrine resistance in breast cancer. Murray JI, West NR, Murphy LC, Watson PH. Endocr Relat Cancer. 2015 Feb;22(1):R51-67. doi: 10.1530/ERC-14-0096. Epub 2014 Nov 17. Review.
  8. A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer. Vollan HK, Rueda OM, Chin SF, Curtis C, Turashvili G, Shah S, Lingjærde OC, Yuan Y, Ng CK, Dunning MJ, Dicks E, Provenzano E, Sammut S, McKinney S, Ellis IO, Pinder S, Purushotham A, Murphy LC, Kristensen VN; METABRIC Group, Brenton JD, Pharoah PD, Børresen-Dale AL, Aparicio S, Caldas C. Mol Oncol. 2015 Jan;9(1):115-27. doi: 10.1016/j.molonc.2014.07.019. Epub 2014 Aug 8.
  9. The kinome associated with estrogen receptor-positive status in human breast cancer. Bruce MC, McAllister D, Murphy LC. Endocr Relat Cancer. 2014 Oct;21(5):R357-70. doi: 10.1530/ERC-14-0232. Epub 2014 Jul 23. Review.
  10. The Mammalian Target for Rapamycin Pathway is Associated with the Phosphorylation Score (P7) for Estrogen Receptor-a in Human Breast Tumors, in vivo. (2014) Anuraag Shrivastav, M Chrissie Bruce, Danira Jaksic, Tarek Bader, Sri Seekallu, Carla Penner, Zoann Nugent, Peter Watson, Leigh Murphy. Breast Cancer Res 16(3):R49
  11. Certification for Biobanks: The Program Developed by the Canadian Tumour Repository Network (CTRNet). A. Matzke, S. O'Donoghue, R.O. Barnes, H. Daudt, S. Cheah, A. Suggitt, J. Bartlett, S. Damaraju, R. Johnston, L. Murphy, L. Shepherd, A.M. Mes-Masson, B. Schacter, P. Watson. (2012) Biopreservation and Biobanking 10/5 : 426-432.
  12. A Framework for Biobank Sustainability. Peter H. Watson, Sara Y. Nussbeck, Candace Carter, Sheila O'Donoghue, Stefanie Cheah, Rebecca Barnes, John Bartlett, Jane Carpenter, William Grizzle, Randy Johnston, Anne-Marie Mes-Masson, Leigh Murphy, Katherine Sexton, Lois Shepherd, Daniel Simeon-Dubach, Nik Zeps, Brent Schacter. (2014) Biopreservation and Biobanking (in press)
  13. splice variant expression in four large cohorts of human breast cancer patient tumors.Breast Wimberly H, Han G, Pinnaduwage D, Murphy LC, Yang XR, Andrulis IL, Sherman M, Figueroa J, Rimm DL. ERß Cancer Res Treat. 2014 Jul 10. [Epub ahead of print]
  14. Preferential Estrogen Receptor ß Ligands Reduce Bcl-2 Expression in Hormone-Resistant Breast Cancer Cells to Increase Autophagy.Ruddy SC, Lau R, Cabrita MA, McGregor C, McKay BC, Murphy LC, Wright JS, Durst T, Pratt MA. Mol Cancer Ther. 2014 Jul;13(7):1882-93. doi: 10.1158/1535-7163.MCT-13-1066. Epub 2014 Apr 30.
  15. Steroid receptor RNA activator protein (SRAP) expression as a prognostic factor in ER+ human breast tumors. Yan Y, Penner CC, Skliris GP, Cooper C, Nugent Z, Blanchard A, Hamedani MK, Wang X, Myal Y, Murphy LC, Leygue E. J Cancer Res Clin Oncol. 2013 Aug 2. [Epub ahead of print]
  16. Claudin 1 expression in basal-like breast cancer is related to patient age. Blanchard AA, Ma X, Dueck KJ, Penner C, Cooper SC, Mulhall D, Murphy LC, Leygue E, Myal Y. BMC Cancer. 2013 May 30;13:268. doi: 10.1186/1471-2407-13-268.
  17. Expression of both Estrogen Receptor-beta 1 (ER-ß1) and its co-regulator Steroid Receptor RNA Activator Protein (SRAP) are predictive for benefit from tamoxifen therapy in patients with Estrogen Receptor-alpha (ER-a)-Negative Early Breast Cancer (EBC). Yan Y, Li X, Blanchard A, Bramwell VH, Pritchard KI, Tu D, Shepherd L, Myal Y, Penner C, Watson PH, Leygue E, Murphy LC. Ann Oncol. 2013 Aug;24(8):1986-93. doi: 10.1093/annonc/mdt132. Epub 2013 Apr 11.
  18. A bi-faceted role of estrogen receptor ß in breast cancer. Leygue E, Murphy LC. Endocr Relat Cancer. 2013 May 30;20(3):R127-39. doi: 10.1530/ERC-12-0389. Print 2013 Jun.
  19. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Gräf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S; METABRIC Group, Langerød A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Børresen-Dale AL, Brenton JD, Tavaré S, Caldas C, Aparicio S. Nature.(2012) Apr 18;486(7403):346-52.
  20. Post-translational modifications of nuclear receptors and human disease. Anbalagan M, Huderson B, Murphy L, Rowan BG.(2012) Nucl Recept Signal. 2012;10:e001. Epub 2012 Feb 27. Review
  21. The role of estrogen receptor-ß in breast cancer.Murphy LC, Leygue E.(2012) Semin Reprod Med. 2012 Jan;30(1):5-13. Epub 2012 Jan 23. Review.
  22. Oncostatin M suppresses oestrogen receptor-a expression and is associated with poor outcome in human breast cancer. West NR, Murphy LC, Watson PH.(2012) Endocr Relat Cancer. 2012 Apr 10;19(2):181-95. Print 2012 Apr.
  23. CARM1 is an important determinant of ERa-dependent breast cancer cell differentiation and proliferation in breast cancer cells.Al-Dhaheri M, Wu J, Skliris GP, Li J, Higashimato K, Wang Y, White KP, Lambert P, Zhu Y, Murphy L, Xu W.(2011) Cancer Res. 2011 Mar 15;71(6):2118-28. Epub 2011 Jan 31.
  24. Clinical significance of estrogen receptor phosphorylation. Murphy LC, Seekallu SV, Watson PH.(2011) Endocr Relat Cancer. 2011 Jan 19;18(1):R1-14. Print 2011 Feb. Review.
  25. Identification of CARM1 as an important determinant of ERa-dependent breast cancer cell differentiation and proliferation. Mariam Al-Dhaheri, George Skliris, Jiacai Wu, Jun Li, Ken Higashimato, Yidan Wang, Kevin White, Yuerong Zhu, Leigh Murphy, Wei Xu. (2011) Cancer Res71(6):2118-28
  26. Estrogen receptor alpha phosphorylated at tyrosine 537 is associated with poor clinical outcome in breast cancer patients treated with tamoxifen. Georgios Skliris, Zoann Nugent, Peter Watson, Leigh Murphy (2010) Hormones and Cancer 1 (4), pp. 215-221.
  27. A phosphorylation code for estrogen receptor alpha predicts clinical outcome to endocrine therapy in breast cancer. Georgios Skliris, Zoann Nugent, Brian Rowan, Carla Penner, Peter Watson, Leigh Murphy.(2010) Endocrine-Related Cancer 17(3):589-97
  28. Assay Development for the Determination of Phosphorylation Stoichiometry using MRM methods with and without Phosphatase Treatment: Application to Breast Cancer Signaling Pathways. Dominik Domanski, Leigh C. Murphy, Christoph H. Borchers Analytical Chemistry 82(13):5610-20
  29. Steroid Receptor RNA Activator Protein (SRAP): a Potential New Prognostic Marker for Estrogen Receptor-positive / Node-Negative / Younger Breast Cancer Patients. Yi Yan, George P. Skliris, Carla C. Penner, Shilpa Chooniedass-Kothari S, Charlton Cooper, Zoann Nugent, Andrea Fristenski, Mohamad K. Hamedani,Anne Blanchard, Yvonne Myal, Leigh C. Murphy, Etienne Leygue (2009) Breast Cancer Res 11(5):R67
  30. Identification of CARM1 as an important determinant of ERa-dependent breast cancer cell differentiation and proliferation. Mariam Al-Dhaheri, George Skliris, Jiacai Wu, Jun Li, Ken Higashimato, Yidan Wang, Kevin White, Yuerong Zhu, Leigh Murphy, Wei Xu. (2011) Cancer Res 71(6):2118-28
  31. Estrogen receptor alpha phosphorylated at tyrosine 537 is associated with poor clinical outcome in breast cancer patients treated with tamoxifen. Georgios Skliris, Zoann Nugent, Peter Watson, Leigh Murphy (2010) Hormones and Cancer 1 (4), pp. 215-221.

Chapters and Invited reviews

  1. Leigh C Murphy, Srivinas Seekallu, Peter H Watson. (2011) Clinical Significance of Estrogen Receptor Phosphorylation. Endocrine-Related Cancer, invited review 2011 Jan 19;18 (1) :R1- R14.
  2. Leygue E, Murphy LC 2011 Comparative evaluation of ER-alpha and ER-beta significance in breast cancer: state of the art. Expert Review of Endocrinology and Metabolism, 6: 333-343 (invited review)
  3. LC.Murphy, G.P.Skliris, B. Rowan, M. Al-Dhaheri, C Williams, C. Penner, S. Troup, S. Begic, Michelle Parisien, P.H.Watson (2009) The Relevance of Phosphorylated Forms of Estrogen Receptor in Human Breast Cancer in vivo . J Steroid Biochem Mol Biology114: 90-95
  4. George P. Skliris, Etienne Leygue , Peter H. Watson, Leigh C. Murphy. (2008) Estrogen receptor alpha negative breast cancer patients: estrogen receptor beta as atherapeutic target. J Steroid Biochem Mol Biology 109 (1-2):1-10. (review)

Funding

CBCF-P/NWT
Determining phospho-ERa cistrome in HBC
$120000/yr
2012-15

CBCF-Prairies/NWT-Opportunity Grant
$10000
2012
CTRNet workshop - Basics of Biobanking

CBCF-P/NWT
Beyond the Estrogen Receptor involvement of mechanistic target of rapamycin (mTOR) in estrogen signaling in normal and malignant human breast epithelial cells.
$125000
2014-17

CIHR(Priority)
Beyond the Estrogen Receptor involvement of kinases in estrogen signaling in normal and malignant human breast epithelial
$100000
2015-2016

AWARDS

2015 Distinguished Professor, University of Manitoba
2015 Nominated by University of Manitoba for membership to the Canadian Academy of Health Sciences. 2015
2007, 2008 Nominated by University of Manitoba Faculty of Medicine for THE HENRY FRIESEN AWARD AND LECTURE-Sponsored by The Canadian Society for Clinical Investigation (CSCI) and The Royal College of Physicians and Surgeons of Canada (RCPSC)
2005 YMCA-YWCA (Winnipeg) Women of Distinction Award in Research, Science, Technology and Environment Category
1998 The University of Manitoba Merit Award for outstanding achievement in Research Activities Category.
1994-1999 MRC (Canada) Scientist
1988 The University of Manitoba Merit Award for outstanding achievement in the Research, Scholarly Work & other Creative Activities category.
July 1988- June 1994 National Cancer Institute(Canada) Research Scientist Award
July 1987 Manitoba Health Research Council Scholarship




RIOH gratefully acknowledges the generous support of



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