Biovitenskap

Deciphering the impact of nuclear architecture dysregulation in breast cancer progression

Breast cancer is the most frequent cancer and the second leading cause of death by cancer worldwide (1). So far, a number of extrinsic and intrinsic breast cancer risk factors have been identified but early molecular mechanisms as well as progression mechanisms remain poorly understood. Alterations of nuclear architecture are frequently reported in different pathologies including breast cancer (2). They can be the consequence of the dysregulation of proteins associated to the nuclear envelope, for example lamins, and/or mechanical strains. Lamins expression is often dysregulated in breast cancer, even at early stages (3). As an example, downregulation of Lamin A/C in mammary  epithelial cells leads to nuclear deformities that are similar to those of breast cancer cells (4). Furthermore, Lamin A/C and Lamin B1 have also a major role in regulating genome organization and gene expression at the nuclear periphery. Indeed Lamin A/C and Lamin B1 can interact with DNA domains called LADs (Lamina Associated Domains), mostly being gene-poor and transcriptionally inactive genomic regions (5).  In this context, we are interested in studying if nuclear architecture defects could have functional consequences in breast cancer pathogenesis and progression, by changing genome organization as well as gene regulation.

In this project, the candidate will investigate: 

-  The  phenotypic consequences of the dysregulation of key nuclear architecture components or other identified partners in breast cancer transformation/progression models

-  The impact of nuclear architecture defects on chromatin organization and  gene regulation from transformation to breast cancer progression

Depending on the student’s interest, bioinformatics approaches can be considered.

Methods:

The student will learn different wet-lab techniques: cell culture (human breast epithelial and cancer cell lines), proliferation assay, anchorage-independent growth assay, cell transfection (plasmids and siRNAs), lentiviral transduction, molecular cloning, Western Blot, confocal microscopy, gene expression analysis (RT-qPCR, RNA-seq).

The student will also be trained to analyse and present results.

 It will be expected that the student:

-  Reads the relevant literature and is driven in understanding the project and making her/his project move forward.

-   Becomes independent in laboratory work after the training period, but do not hesitate to ask for help when needed.

-   Regularly reports on his/her project during lab meetings.

 

This project will take place at the Faculty of Medicine, Department of Basic Medical Sciences, Nuclear Architecture in Adipose and Cancer Stem Cells group (Pr. P Collas). The student will be supervised by Dr. Aurélie Bellanger.

https://www.med.uio.no/imb/english/research/groups/chromatin-regulation-stem-cells/

http://collaslab.org/

 

Contact: Aurélie Bellanger,  a.n.p.bellanger@medisin.uio.no

Supervisor : Aurélie Bellanger

Internal supervisor (IBV) : Pierre Chymkowitch

References

1.            Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-49.

2.            Zink D, Fischer AH, Nickerson JA. Nuclear structure in cancer cells. Nat Rev Cancer. 2004;4(9):677-87.

3.            Alhudiri IM, Nolan CC, Ellis IO, Elzagheid A, Rakha EA, Green AR, et al. Expression of Lamin A/C in early-stage breast cancer and its prognostic value. Breast Cancer Res Treat. 2019;174(3):661-8.

4.            Capo-chichi CD, Cai KQ, Smedberg J, Ganjei-Azar P, Godwin AK, Xu XX. Loss of A-type lamin expression compromises nuclear envelope integrity in breast cancer. Chin J Cancer. 2011;30(6):415-25.

5.            Lochs SJA, Kefalopoulou S, Kind J. Lamina Associated Domains and Gene Regulation in Development and Cancer. Cells. 2019;8(3).

Publisert 8. sep. 2021 13:07 - Sist endret 8. sep. 2021 13:07

Veileder(e)

Omfang (studiepoeng)

60

Intern veileder: Pierre Chymkowitch