Breast Cancer Biology

The aim of our laboratory is to understand the molecular pathology of breast cancer to identify new therapeutic targets. We are evaluating the therapeutic potential of targeting enzymes mediating post-translational modifications that are overexpressed/activated in breast cancer compared to normal breast tissues. We are currently focusing on the family of protein arginine methyltransferases (PRMTs).

Breast cancer is one of the leading causes of death in women, with 50,000 new cases in France per year and 1.7 million worldwide. The subtype of breast cancer known as triple-negative (TNBC) is characterized by a lack of estrogen receptor and progesterone receptor expression, and lack of HER2 overexpression. TNBC is the most aggressive breast cancer subtype and remains the most challenging breast cancer to treat. Although TNBC patients respond initially well to chemotherapies, they often succumb due to high rate of relapses resulting from drug-resistant tumor cells, and metastasis formation. Their characteristic inter-tumor and intra-tumor heterogeneity pose a major challenge in the development of effective treatment strategies. Consequently, very few targeted therapies (PARP and immune checkpoint inhibitors, sacituzumab govitecan) have been FDA-approved, but only for subsets of TNBC patients. Therefore, our objective is to pinpoint novel therapeutic targets for the management of a larger number of TNBC patients.

To achieve this aim, we have previously performed microarrays (DNA, RNA, microRNA, and protein) on a cohort of 200 samples including biopsies of the different breast cancer subgroups, healthy breast tissues and TNBC cell lines. Bioinformatics analyses have identified numerous candidate therapeutic targets including post-translational modifying enzymes.  Post-translational modifications (PTMs) regulate many biological processes such as gene expression, protein-protein interactions, subcellular localization, protein stability, and signal transduction. The deregulation of enzymes controlling PTMs is a hallmark of cancer as it can lead to the stimulation of oncogenic pathways, such as the PI3K/AKT pathway which is activated in many cancer types. We initially focused on kinases (PI3K/AKT, TTK, AXL, and PLK1) and one of our studies (TTK) led to a phase I/II clinical trial conducted by a pharmaceutical company. We also evaluated the potential of targeting the WNT signaling pathway, which is highly regulated by PTMs, activated in TNBC, and potentially responsible for drug resistance.

Several protein methyltransferases are over-expressed in different cancer types, including breast cancer, and are emerging as attractive new therapeutic targets. Protein methyltransferases catalyze the transfer of methyl group(s) to the arginine (protein arginine methyltransferases, PRMTs) or the lysine (lysine methyltransferases, KMTs) of their substrates (histones and many nuclear and cytosolic proteins). PRMTs regulate transcription, pre-mRNA splicing, embryo development, DNA repair, stemness properties, migration, and invasion. Our laboratory is currently focusing on several PRMTs that we found to be overexpressed in TNBC compared to normal breast tissues. We are evaluating their potential as therapeutic targets alone or in combination with drugs (chemo- and targeted-therapies) currently used to treat TNBC patients. We also aim to better characterize their functions of PRMTs by unveiling their partners/substrates and examining the functional impact of their methylation.

BCBG is part of the Translational Research Department since its creation in 2005 and is co-affiliated since 2021 to the Cell Biology and Cancer Unit (CNRS UMR144) within the team of Dr Philippe Chavrier (Membrane and Cytoskeleton Dynamics).

Keywords: breast cancer; triple-negative breast cancer; therapeutic target; post-translational modification; phosphorylation; protein kinase; protein methylation; protein arginine methyltransferase; PTM; PRMTs; KMTs; CARM1; PRMT1; PRMT5