Public Thesis defense - LIBST

Molecular and functional interactions between HOXA1, NF-κB and ERα in breast cancer by Magali BELPAIRE

Pour l’obtention du grade de Docteur en sciences

Breast cancer is a heterogeneous disease and the leading cause of female cancer mortality worldwide. About 70% of breast cancers express the estrogen receptor α (ERα). ERα is a transcription factor essential for mammary gland development, but also a key player in breast oncogenesis. Despite the efforts aiming at preventing ERα-mediated tumour progression by applying endocrine therapies, resistance to such treatments often occurs. It is therefore crucial to investigate the mode of action of breast oncogenes and their relationships with ERα. HOX proteins, a family of master regulators of embryo development, have emerged as being important players in oncogenesis. In particular, HOXA1 was demonstrated to act as a breast oncogene. Here, we present breast cancer transcriptome analyses pointing out an extremely strong negative correlation between genes associated with HOXA1 versus ER expression status. We identified 2486 genes whose expression is supportive of a functional antagonism between HOXA1 and ERα. From this starting observation, we demonstrated in vitro that HOXA1 can inhibit ERα activity and that the HOXA1 action towards ERα is at least bimodal. It requires an intact DNA-binding homeodomain but also the DNA-binding independent capacity of HOXA1 to activate NF-κB. We also showed that ERα inhibition does not require the HOXA1-PBX interaction previously shown to be critical for the transcriptional activity of HOXA1. Finally, we revealed that HOXA1 and ERα can physically interact in the cell nucleus but that this interaction is not essential for the HOXA1-mediated inhibition of ERα. Taken together with in silico data and the published literature, our results support that HOXA1 is an important breast cancer driver which has the ability of taking the lead of the oncogenic process in part by inhibiting ERα.

Jury members :

• Prof. René Rezsohazy (UCLouvain), supervisor
• Prof. Jean-François Baurain (UCLouvain), supervisor
• Prof. Bernard Hallet (UCLouvain), chairperson
• Prof. Patrick Dumont (UCLouvain), secretary
• Prof. Melissa Page (UCLouvain)
• Prof. Christel Péqueux (ULiège, Belgium)
• Prof. Alexander Thompson (University of Nottingham, UK)

Pay attention :

The public defense of Magali Belpaire scheduled for Friday 30 October at 16:15 will take place in the form of a video conference Teams

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