BCI Centre Grant
Reporting period Jan 2014 - Oct 2015
Phenomenal advances in targeted therapy over the past ten years have had a significant
impact on breast cancer survival. Within these excellent survival rates however lie a
significant group of patients (>30%) who will have disease recurrence. The challenge now is
to understand the pathophysiology of acquired endocrine resistance to ensure that metastatic
disease is detected early and treated effectively. Uncovering the key mechanisms of
resistance will provide predictive markers of disease recurrence which will enable us to tailor
existing therapies to improve outcome in specific patient groups within ten years.
Using next generation sequencing our group have uncovered new biomarkers which have the
potential to predict the efficacy of endocrine therapy in breast cancer patients. These
biomarkers are currently in a multi-centre national clinical trial to assess their strength to
predict outcome on tamoxifen and aromatase inhibitor therapy in patients with estrogen
receptor (ER) positive disease. Our group is collaborating with ALMAC, the multi-national
diagnostic company to bring these biomarker assays into clinical use.
Currently there is no targeted treatment for ER-positive metastatic breast cancer. Our group
have identified a cell surface therapeutic target which provides the opportunity to develop
new treatment strategies. A new small peptide is currently in pre-clinical assessment in our
laboratories to investigate its efficacy in treating metastatic disease. This new drug along with
its specific companion diagnostic has clear advantages over current clinical management of
ER positive metastatic breast cancer. We are planning to develop this new therapeutic to
treat metastatic breast cancer with our pharmaceutical partners, Pfizer commencing January
2016.
Our research is conducted by a translational team of clinicians and research scientists. Part of
our mission is to train the next generation of clinical researchers. Jarlath Bolger and Damir
Vareslija were awarded their PhDs for research supported by Breast Cancer Ireland. Both
Jarlath and Damir have published their work in high impact journals and are continuing to
conduct research into the causes of resistance to therapy in breast cancer patients. This year
we have hired a new post-doctoral researcher Sara Charmsaz and a clinical PhD student
Aziemah Ali.
Specific Outputs
Publications
Ali A, Creevey L, Hao Y, McCartan D, O'Gaora P, Hill A, Young L, McIlroy M. Prosaposin
activates the androgen receptor and potentiates resistance to endocrine treatment in breast
cancer. Breast Cancer Res. 2015 Sep 4;17(1):123.
McBryan J, Fagan A, McCartan D, Bane FT, Varešlija D, Cocchiglia S, Byrne C, Bolger J,
McIlroy M, Hudson L, Tibbitts P, Ó Gaora P, Hill AD, Young LS. Transcriptomic Profiling
of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic
Expression Changes Following Endocrine Therapy. Clin Cancer Res. 2015 Aug 3.
Nelson L, McKeen HD, Marshall A, Mulrane L, Starczynski J, Storr SJ, Lanigan F, Byrne C,
Arthur K, Hegarty S, Ali AA, Furlong F, McCarthy HO, Ellis IO, Green AR, Rakha E,
Young L, Kunkler I, Thomas J, Jack W, Cameron D, Jirström K, Yakkundi A, McClements
L, Martin SG, Gallagher WM, Dunn J, Bartlett J, O'Connor D, Robson T. FKBPL: a marker
of good prognosis in breast cancer. Oncotarget. 2015 May 20;6(14):12209-23.
Pathiraja TN, Nayak SR, Xi Y, Jiang S, Garee JP, Edwards DP, Lee AV, Chen J, Shea MJ,
Santen RJ, Gannon F, Kangaspeska S, Jelinek J, Issa JP, Richer JK, Elias A, McIlroy M,
Young LS, Davidson NE, Schiff R, Li W, Oesterreich S. Epigenetic reprogramming of
HOXC10 in endocrine-resistant breast cancer. Sci Transl Med. 2014 Mar 26;6(229):229ra41.
McFarlane S, Coulter JA, Tibbits P, O'Grady A, McFarlane C, Montgomery N, Hill A,
McCarthy HO, Young LS, Kay EW, Isacke CM, Waugh DJ. CD44 increases the efficiency
of distant metastasis of breast cancer. Oncotarget. 2015 May 10;6(13):11465-76
Genomic interaction between ER and HMGB2 identifies DDX18 as a novel driver of
endocrine resistance in breast cancer cells. Redmond AM, Byrne C, Bane FT, Brown GD,
Tibbitts P, O'Brien K, Hill AD, Carroll JS, Young LS. Oncogene. 2014 Oct 6. doi:
10.1038/onc.2014.323.
NCOA1 Directly Targets M-CSF1 Expression to Promote Breast Cancer Metastasis. Qin L,
Wu YL, Toneff MJ, Li D, Liao L, Gao X, Bane FT, Tien JC, Xu Y, Feng Z, Yang Z, Xu Y,
Theissen SM, Li Y, Young L, Xu J. Cancer Res. 2014 Jul 1;74(13):3477-88. doi:
10.1158/0008-5472.CAN-13-2639.
Global gene repression by the steroid receptor coactivator SRC-1 promotes oncogenesis.
Walsh CA, Bolger JC, Byrne C, Cocchiglia S, Hao Y, Fagan A, Qin L, Cahalin A, McCartan
D, McIlroy M, O'Gaora P, Xu J, Hill AD, Young LS. Cancer Res. 2014 May 1;74(9):253344. doi: 10.1158/0008-5472.CAN-13-2133.
Growth factor receptor/steroid receptor cross talk in trastuzumab-treated breast cancer.
Collins DC, Cocchiglia S, Tibbitts P, Solon G, Bane FT, McBryan J, Treumann A, Eustace
A, Hennessy B, Hill AD, Young LS. Oncogene. 2015 Jan 22;34(4):525-30. doi:
10.1038/onc.2013.586. Epub 2014 Jan 27.
Book Chapters:
ADAM22 as a prognostic and therapeutic drug target in the treatment of endocrine-resistant
breast cancer. Bolger JC, Young LS.
Vitam Horm. 2013;93:307-21. doi: 10.1016/B978-0-12-416673-8.00014-9. Review.
Ligand-independent signaling through estrogen receptor pathways in breast cancer
Jean McBryan and Leonie S. Young
Resistance to Aromatase Inhibitors in Breast Cancer, in press
PhD Graduations 2014
Damir Vareslija: Estrogen independent ER signalling in aromatase inhibitor resistant breast
cancer is target gene specific
Jarlath Bolger: Investigating novel mechanisms of metastasis in endocrine resistant breast
cancer.
Left to right: Professor Arnold Hill, Dr Jarlath Bolger, Professor Leonie Young and Dr Marie
McIlroy
Invited Presentation: 2014
Professor Leonie Young was invited to speak at the Endocrine Society ICE/ENDO 2014
which was held in Chicago in June 2014.
Professor Leonie Young was invited to speak at the Break-Through Breast Cancer at
Manchester Breast Centre, February 2014.
Oral Presentations: 2014
Azlena Ali: Oral Presentation in the Patey Prize category inSociety of Academic & Research
Surgery (SARS) conference on 8-9th January 2014 in Cambridge, UK
Azlena Ali: Oral Presentation in the Plenary Prize category in Sylvester O’Halloran Scientific
Surgical Symposium on 28th February-1st March 2014 in Limerick, Ireland
Azlena Ali: Oral Presentation in the Registrar’s Prize category at RAMI-Section for Surgery
on 4th April 2014 in RCSI, Dublin
Azlena Ali: Oral presentation in SARS meeting 7th January-8th January 2015 in Durham, UK
Azlena Ali: Accepted for Oral presentation in the Plenary Prize category in Sylvester
O’Halloran meeting on 6th March 2015 in Limerick, Ireland
Damir Vareslija: Oral presentation in IACR 27-28th February 2014 in Galway, Ireland
Damir Vareslija: Breast Predict, Conway Institute, September 2014
Poster Presentations:
Azlena Ali: Display Poster presentation in IACR 27-28th February 2014 in Galway, Ireland
Jean Mc Bryan: Display poster at The 2014 San Antonio Breast Cancer Symposium,
December 2014
Damir Vareslija: Display poster at The 2014 San Antonio Breast Cancer Symposium,
December 2014