Description of the PhD thesis project
The poor prognosis-associated triple-negative
breast cancer (TNBC) remains a major challenge for oncologists. A better
understanding of the biology of TNBC could lead to new therapeutic strategies.
We have found that some protein arginine
methyltransferases (PRMTs), which catalyze the methylation of arginine residues
within proteins, are more expressed in TNBC compared to normal breast tissues,
thus representing potential therapeutic targets.
PRMT4, better known as CARM1 is overexpressed
in various tumors compared to normal tissues, and a hotspot mutation in CARM1
supports it as a cancer driver gene. Specific CARM1 inhibitors display
anti-tumor activity in hematopoietic cancers. Among the different breast cancer
types, CARM1 has been extensively studied in luminal breast cancer due to its
role in activating estrogen receptor signaling pathway. Very little is known
about the role of CARM1 in TNBC apart from promoting cell migration.
Two CARM1 variants are expressed in breast
cancers: a full-length form (CARM1-FL) and a shorter spliced isoform
(CARM1-ΔE15). CARM1-ΔE15 has been proposed to be the oncogenic form of CARM1,
and is the most abundant form of CARM1 (about 80%) in breast cancers. However,
only very few studies have explored the functions of CARM1-ΔE15 in cells.
Indeed, CARM1-ΔE15 has not been taken into account in most CARM1 studies. So
far, only one substrate has been reported to be methylated specifically by
CARM1-ΔE15, and not by CARM1-FL, showing that both CARM1 forms can have
specific functions. Concordantly, a recent study performed in our laboratory
identified potential specific protein partners for CARM1-ΔE15.
program aims to decipher the specific functions of CARM1-ΔE15, the main CARM1
isoform expressed in breast cancers, by searching for specific
partners/substrates of both CARM1-ΔE15 and CARM1-FL. The candidate will focus
on few of them for further analyses, in particular by studying the impact of
methylation on their functions.
International, interdisciplinary &
intersectoral aspects of the project
The thesis program combines basic and
translational research. It will benefit of an international mentor (Canada) who
is internationally recognized as an expert on the field of PRMTs.
The project will also benefit of an
industrial mentor who is an expert of translational research and cell signalling.
The research project involves different
domains: biochemistry, cell biology, RNA metabolism, tumor biology.
1. Meseure D, Vacher S, Boudjemaa S, Marick L,
Nicolas A, Leclere R, Chemlali W, Champenois G, Schnitzler A, Lesage L, Dubois T, Bieche I (2020)
Biopathological significance of PIWI-PiRNA pathway deregulation in invasive
breast carcinomas. Cancers, 12, 2833
2. Zajac O, Leclerc R, Nicolas A, Meseure D,
Marchiò C, Vincent-Salomon A, Roman-Roman S, Schoumacher M, Dubois T (2020) AXL controls directed
migration of mesenchymal triple-negative breast cancer cells. Cells 9, pii:
3. Maire V, Mahmood F, Rigaill G, Ye M, Brisson
A, Némati F, Gentien D, Tucker GC, Roman-Roman S, Dubois T (2019) LRP8 is overexpressed in estrogen-negative breast
cancers and a potential target for these tumors. Cancer Medicine 8,
4. Vinet M, Suresh S, Maire V, Monchecourt C,
Némati F, Lesage L, Pierre F, Ye M, Lescure A, Brisson A, Meseure D, Nicolas A,
Rigaill G, Marangoni E, Del Nery E, Roman-Roman S, Dubois T (2019) Protein Arginine Methyltransferase 5: a novel
therapeutic target for triple-negative breast cancers. Cancer Medicine 8,
5. Maubant S, Tahtouh T, Brisson A, Maire V,
Némati F, Tesson B, Ye M, Rigaill G, Noizet M, Dumont A, Gentien D,
Marty-Prouvost B, de Koning L, Mahmood SF, Decaudin D, Cruzalegui F, Tucker GC,
Roman-Roman S, Dubois T (2018) LRP5
regulates the expression of STK40, a new potential target in triple-negative
breast cancers. Oncotarget, 9, 22586-22604