Daria Bulanova's doctoral thesis pinpoints GPRC5A as a novel breast cancer gene

Breast cancer is the most common cancer in women. Some of the familial breast cancers are caused by mutations in well-known tumor suppressor genes that help repair damaged DNA. However, a large proportion of familial breast cancer predisposition is not explained by the known genes, such as BRCA1 and BRCA2 and thus further genetic risk factors must exist.

The main aim of M.Sc. Daria Bulanova’s thesis entitled "Novel Genetic Determinants of Breast Cancer Progression", was to identify these new breast-cancer predisposing mutations and to elucidate the biological mechanisms underlying these genetic findings. She will defend her doctoral dissertation in the Faculty of Biological and Environmental Sciences on 5 December.

Daria graduated from the Kazan Federal University, Russia, in 2011 with microbiology and molecular biology as her major subjects. When looking for PhD positions abroad, she got interested in FIMM-EMBL Group Leader Sergey Kuznetsov’s work, contacted him directly, and, after successful interviews, started at FIMM the same autumn.

Daria’s thesis consists of three publications. First, in collaboration with Prof. Imyanitov Lab at N.N.Petrov Institute of Oncology, St.Petersburg, she identified a promising mutation in an orphan G protein-coupled receptor-encoding gene GPRC5A using modern exome sequencing technologies. In the second publication, she explored the effect of GPRC5A deficiency on cancer progression. The third article describes drug sensitivity of BRCA1-decifient cell lines.

Interestingly, the identified mutation was found to be overrepresented among patients with BRCA1 mutation. Thus we focused our further efforts on studying the interaction of these two proteins and were able to show that GPRC5A modulates both the expression and function of BRCA1.

- Daria Bulanova

The work was complicated by the fact that basically nothing was known about the function of the gene or the GPRC5A-protein in breast cancer at the time when the mutation was identified. The protein has seven transmembrane domains and structurally looks like a glutamate receptor.

We were surprised to found that the protein modulates cellular adhesion. Even more surprisingly, this effect seems to be tissue type specific: for example, we see it in breast and cervical cancer cell lines, but not in lung cancer cell lines. To me, this completely unexpected function of the protein as well as the tissue specificity we observed were the most exciting findings of my thesis.

The more we learned about the protein, the more it stimulated our curiosity. Why precisely this protein but none of the very similar ones is overexpressed in cancer?

Hopefully some of these open questions will be answered by future collaborative studies that will focus on the role of GPRC5A in ovarian cancer.

We all know that to be a successful researcher, it is necessary to work hard. What I have found out during my thesis project is that when you do that while being surrounded by nice people, it is much less painful. The community is as important as the PhD project and the supervisors and I am grateful to the FIMM community, especially the people in my wing and FIMM’s Research Training Coordinator Gretchen Repasky, for their support.

When asked about the personal characteristics that have helped her to complete the thesis project, Daria brings up her good time-management skills. The fact that she is also a mother of a 1.5 years old kid and started to work part-time in the lab when the baby was only three weeks of age truly speak for that!  

After careful consideration, Daria decided to continue her Post-Doctoral studies at FIMM, in the group of FIMM-EMBL Group Leader Krister Wennerberg. The aim of her project is to develop new ways to quantify drug sensitivity and resistance in ovarian cancer.

It might have been better for my CV to work at some other research institute, but both the project Krister had to offer and the great team he has, convinced me to continue here at FIMM. I believe many interesting discoveries are ahead.

The public examination of Daria Bulanova’s thesis will take place on 5 December 2016 at 12 o’clock noon in the lecture hall 1 of Haartman Institute, Haartmaninkatu 3. Professor Thorarinn Gudjonsson (University of Iceland) will serve as the opponent and Professor Minna Nyström as the custos.

The dissertation is also available in electronic form and can be downloaded here.