Ahmet Ucar is working on murine models to dissect molecular pathways involved in the regulation of stem cells during breast development and breast tumourigenesis. A particular focus of his research is to better characterise the mammary epithelial and breast cancer stem cells with the aim of developing specific stem cell-targeted therapies for different breast cancer subtypes.

Research Fellow

The University of Manchester
Michael Smith Building
Oxford Road
Manchester
M13 9PT

Tel: +44 (0)161 3067116

Email: ahmet.ucar@manchester.ac.uk

I have obtained my BSc (1999) and MSc (2001) degrees in the Department of Molecular Biology and Genetics at Bilkent University, Turkey. During this time, I completed my BSc thesis in Cancer Genetics in the lab of Prof Tayfun Ozcelik and my MSc thesis in Molecular Physiology in the lab of Dr Can Akcali. I then joined the group of Prof Peter Gruss for my PhD studies at the Max Planck Institute for Biophysical Chemistry in Goettingen, Germany. I received my PhD degree (2007) on a thesis project that aimed to elucidate the role of axon guidance receptors during the embryonic development of the brain in murine models.

In my first postdoctoral position (2007-2009), I worked in the group of Dr Kamal Chowdhury at the same Max Planck Institute to elucidate the role of the microRNA-212/132 in the development of mammary gland and brain as well as during the pathology of the cardiac failure. Afterwards, I joined the group of Dr Thomas Hoffmann at the German Cancer Research Centre (DKFZ) in Heidelberg, Germany, (2010-2012) to study the role of Hipk2 in mammary epithelial and breast cancer stem cells. Subsequently, I joined the group of Prof Bruno Kyewski at DKFZ as a senior postdoc (2012-2014) to identify and characterise the thymic epithelial stem cells.

In 2014 I joined the group of Prof Charles Streuli at the University of Manchester as a Research Associate (2014-2016) and studied the role of Rac1 signalling in breast cancer stem cells.

In 2016 I have been awarded a prestigious Scientific Fellowship from Breast Cancer Now, which allowed me to set up my own lab in January 2017 at the University of Manchester. The research focus of my lab will be to dissect molecular pathways involved in the regulation of stem cells during breast development and breast tumourigenesis. A particular focus of my current and future work will be to identify exclusive and comprehensive stem cell markers for both the mammary epithelial stem cells and breast cancer stem cells and to develop specific stem cell-targeted therapies for different breast cancer subtypes.

1. Simoes BM., O’Brien CS., Eyre R., Silva A., Yu L., Sarmiento-Castro A., Alferez DG., Spence K., Santiago-Gomez A., Chemi F., Acar A., Gandhi A., Howell A., Brennan K., Ryden L., Catalano S., Ando S., Gee J., Ucar A., Sims AH., Marangoni E., Farnie G., Landberg G., Howell SJ., Clarke RB. Anti-estrogen resistance in human breast tumors is driven by JAG1-NOTCH4-dependent cancer stem cell activity. Cell Reports (2015) 12:1968-1977.
2. Ucar A., Ucar O., Klug P., Brunk F., Matt S., Hofmann TG., Kyewski B. Adult thymus contains FoxN1-negative sphere-forming epithelial stem cells. Immunity (2014) 41:257-269.
3. Ucar A. and Streuli C. A role for ß3-integrins in linking breast development and cancer. Dev Cell (2014) 30:251-252.
4. Kumarswamy R., Volkmann I., Beermann J., Napp LC., Jabs O., Bhayadia R., Melk A., Ucar A., Chowdhury K., Lorenzen JM., Gupta SK.,Batkai S., Thum T. Vascular importance of the miR-212/132 cluster. European Heart J. (2014) 35: 3224-31.
5. Ucar A.*, Erikci E., Ucar O., Chowdhury K.* miR-212 and miR-132 are dispensable for mouse mammary gland development.Reply. Nature Genetics (2014) 46: 804-805. (*: Corresponding author)
6. Ucar A., Gupta SK., Fiedler J., Erikci E., Kardasinski M, Batkai S., Dangwal S., Kumarswamy R., Bang C., Holzmann A., Remke J., Caprio M., Jentzsch C., Engelhardt S., Geisendorf S., Glas C., Hofmann TG., Nessling M., Richter K., Schiffer M., Carrier L., Napp LC., Bauersachs J., Chowdhury K., Thum T. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nature Communications (2012) 25: 3:1078.
7. Ucar A*, Vafaizadeh V., Chowdhury K., Groner B*. MicroRNA-dependent regulation of the microenvironment and the epithelial stromal cell interactions in the mouse mammary gland. Cell Cycle (2011) 10(4): 563-565 (*: Corresponding author)
8. Ucar A, Vafaizadeh V., Jarry H., Klemmt P., Groner B., Chowdhury K. MiR-212 and miR-132 are required for epithelial stromal interactions necessary for mouse mammary gland development. Nature Genetics (2010) 42(12): 1101-8.
9. Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Batolomeo S, Nardacci R, Corazzari M, Fuoco C, Ucar A, Schwartz P, Gruss P, Piacentini M, Chowdhury K, Cecconi F. Ambra1 regulates autophagy and development of the nervous system. Nature (2007) 447(7148): 1121-5.
10. Akcali KC., Dalgic A., Ucar A., Haj KB., Guvenc D. Expression of bcl-2 gene family during resection induced liver regeneration: comparison between hepatectomized and sham groups. World J Gastroenterol. (2004) 10(2): 279-83.
11. Toruner GA., Ucar A., Tez M., Cetinkaya M., Ozen H., Ozcelik T. P53 codon 72 polymorphism in bladder cancer- no evidence of association with increased risk or invasiveness. Urol Res. (2001) 29(6): 393-5.
12. Toruner GA., Akyerli C., Ucar A., Aki T., Atsu N., Ozen H., Tez M., Cetinkaya M., Ozcelik T. Polymorphisms of glutathione S-transferase genes (GSTM1, GSTP1, and GSTT1) and bladder cancer susceptibility in the Turkish population. Arch Toxicol. (2001) 75(8): 459-64

The aim of our research is to extend our current knowledge on mammary epithelial and breast cancer stem cells and to elucidate molecular pathways involved in their regulation during breast development and breast tumourigenesis. This will consequently help to devise novel therapeutic approaches that can target cancer stem cell populations within breast tumours that are known to be therapy resistant and the major driving force of both the tumour recurrence and the metastatic spread of tumours. Currently we have four projects running in our group:

• The stem cell markers that are currently in use for identifying mammary epithelial or breast cancer stem cells help to enrich for these stem cells rather than define a pure stem cell population. Moreover, none of these available markers fully satisfy the definition of a cell-type marker, as they are neither exclusive nor comprehensive. In our group, we have recently developed a genetic approach that will allow us to identify genuine stem cell markers using both established cell lines and the primary human and murine breast epithelial and breast tumour cells.
• Oncogenes are defined as the genes that can transform a normal cell into a cancer cell. One of the well-studied oncogenes in breast cancer is the Her2 (Neu). However it is still unclear how abrupt expression of the Neu oncogene plays a role in the appearance of the breast cancer stem cell population. Moreover, the cell-of-origin of breast cancer stem cells is still under debate, even though some studies suggest the luminal progenitors as the cells-of-origin. In our group, we constructed in vivo models to answer these questions and elucidate the cellular mechanisms of how the Neu oncogene expression can transform the normal mammary epithelial cells into breast cancer stem cells.
• We have identified Rac1 and its splice variant Rac1b as important regulators of the breast cancer stem cell activity by using human breast cancer cell lines. Currently we are using in vivo murine models to further investigate the roles of Rac1 and Rac1b variants in the initiation and progression of breast tumourigenesis as well as their functional involvement during the normal breast development.
• P-Rex1 is a guanine nucleotide exchange factor (GEF) responsible for the activation of Rac1 downstream of PI3K and G-protein signalling pathways. Recently it has been shown that P-Rex1 is highly expressed in ER+ and Her2+ breast tumours. Our earlier work demonstrated that P-Rex1 may have crucial roles in defining stemness of breast cancer stem cells in vitro. Currently we are addressing whether P-Rex1 may have similar functional roles in mammary epithelial stem cells and breast cancer stem cells in vivo using murine models.