Key pathways driving normal mammary development are often hijacked and subverted by the carcinogenic process. This is the case for the ETS transcription factor Elf5, a master regulator of mammary alveolar development that specifies the formation of the estrogen receptor negative (ER-) secretory lineage during pregnancy. We have recently discovered that Elf5 acts during the specification of the basal breast cancer subtype by opposing estrogen action via direct transcriptional repression of FoxA1. This mechanism is also apparent in luminal breast cancer cells that have become resistant to anti-estrogen therapy.
Basal and estrogen resistant breast cancers are characterised by a higher risk of metastasis and poor prognosis. Our group is investigating the role of Elf5 in tumour development from two different perspectives, i) cell autonomous effects of Elf5 in hormone sensitivity suppression and therapy resistance; and ii) the effect of Elf5 in the tumour microenvironment, and in particular in the infiltrated immune system, a major component of tumour microenvironment-induced metastasis.
Our findings suggest that suppression of Elf5 in breast cancer may act to maintain sensitivity to antiestrogens and simultaneously suppress the metastatic phenotype in luminal A breast cancers. Patterns of Elf5 expression may provide a marker predicting antiestrogen-insensitive metastasis in luminal breast cancer.
CL Piggin, DL Roden, D Gallego-Ortega, HJ Lee, SR Oakes and CJ Ormandy. ELF5 isoform expression is tissue-specific and significantly altered in cancer. Breast Cancer Res 2016, Jan 7;18(1):4. doi: 10.1186/s13058-015-0666-0.
D Gallego-Ortega, A Ledger, DL Roden, AMK Law, A Magenau, Z Kikhtyak, C Cho, SL Allerdice, HJ Lee, F Valdes-Mora, D Herrmann, R Salomon, AIJ Young, BY Lee, CM Sergio, W Kaplan, C Piggin, JRW Conway, B Rabinovich, EKA Millar, SR Oakes, T Chtanova, A Swarbrick, MJ Naylor, S O’Toole, AR Green, P Timpson, JMW Gee, IO Ellis, SJ Clark and #CJ Ormandy. ELF5 drives lung metastasis in luminal breast cancer through recruitment of Gr1+ CD11b+ myeloid-derived suppressor cells. PLoS Biol. 2015 Dec 30;13(12):e1002330.
Z Erami, D Herrmann, M Nobis, EJ McGhee, W Leung, N Reischmann, A Mrowinska, JP Schwarz, S Kadir, JRW Conway, SA Karim, C Steele, D Morran, D Gallego-Ortega, A Magenau, RA Ridgway, AKM Law, SN Walters, ST Grey, L Zhang, H Herzog, EC Hardeman, PW Gunning, CJ Ormandy, TRJ Evans, D Strathdee, OJ Sansom, JP Morton, KI Anderson and P Timpson. Intravital FRAP imaging using an E-cadherin-GFP mouse reveals disease and drug-dependent dynamic regulation of cell-cell junctions in live tissue. Cell Rep. 2015 Dec 22. pii: S2211-1247(15)01433-3
Junankar S, *Baker LA, *Roden DL, Nair R, Elsworth B, Gallego-Ortega D, Lacaze P, Cazet A, Nikolic I, Teo WS, Yang J, McFarland A, Harvey K, Naylor MJ, Lakhani SR, Simpson PT, Raghavendra A, Saunus J, Madore J, Kaplan W, Ormandy C, Millar EK, O'Toole S, Yun K, Swarbrick A. ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype. Nat Commun. 2015 Mar 27;6:6548. (* Contributed equally)
*Oakes SR., *Gallego-Ortega D. and Ormandy CJ. The mammary cellular hierarchy and breast cancer. Cell Mol Life Sci. 2014 Nov;71(22):4301-24. (* Contributed equally)
D. Gallego-Ortega, SR. Oakes, HJ. Lee, CL. Piggin, CJ. Ormandy. ELF5, normal mammary development and the heterogeneous phenotypes of breast cancer. Breast Cancer Management, 2013; 2(6):489-498.
Stone, MJ. Cowley, F. Valdes-Mora, RA. McCloy, CM. Sergio, D. Gallego-Ortega, CE Caldon, CJ. Ormandy, AV. Biankin, JMW Gee, RI. Nicholson, CG. Print, SJ. Clark, RL. Sutherland and EA. Musgrove. BCL-2 hypermethylation is a potential biomarker of sensitivity to anti-mitotic chemotherapy in endocrine-resistant breast cancer. Mol Cancer Ther. 2013; 12(9):1874-85.
HJ. Lee, D. Gallego-Ortega, A. Ledger, D. Schramek, P. Joshi, MM. Swarc, C. Cho, JP. Lydon, R. Khokha, JM. Penninger, and CJ. Ormandy. Progesterone drives mammary secretory differentiation via RankL-induction of Elf5 in luminal progenitor cells. Development. 2013; 140(7):1397-401.
DR. Croucher, F. Hochgräfe, L. Zhang, L. Liu, RJ. Lyons, D. Rickwood, CM. Tactacan, BC. Browne, N. Ali, H. Chan, RF. Shearer, D. Gallego-Ortega, DN. Saunders, A. Swarbrick and R. Daly. A novel signaling pathway in basal breast cancer involving Lyn and the atypical kinase SgK269/PEAK1. Cancer Res. 2013; 73(6):1969-80
*M. Kalyuga - *D. Gallego-Ortega, H. Lee, M. Cowley, CE. Caldon, A. Stone, S. Allerdice, F. Valdes-Mora, R. Launchbury, A. Statham, N. Armstrong, C. Alles, A. Young, A. Egger, W. Au, C. Piggin, C. Evans, T. Brummer, W. Kaplan, JMW. Gee, RI. Nicholson, RL. Sutherland, A. Swarbrick, MJ. Naylor, S. Clark, J. Carroll and CJ. Ormandy. ELF5 transcriptionally specifies basal from luminal breast cancer and underpins the acquisition of antiestrogen resistance. PLoS Biol. 2012;10(12):e1001461. (*Joint first authors).
C. Ortiz Padilla, D. Gallego-Ortega, BC. Browne, F. Hochgräfe, CE. Caldon, RJ. Lyons, DR. Croucher, D. Rickwood, CJ. Ormandy, T. Brummerand RJ. Daly. Functional characterization of cancer-associated Gab1 mutation. Oncogene. 2013; 23;32(21):2696-702.
*HJ. Lee - RA. Hinshelwood, T. Bouras, D. Gallego-Ortega, F. Valdes-Mora, JE. Visvader, ^SJ Clark and ^CJ. Ormandy. Lineage Specific Methylation of the Elf5 Promoter in Mammary Epithelial Cells. Stem Cells, 2011; 29(10):1611-9. (^* Contributed equally)
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