Drivers and suppressors of triple-negative breast cancer
Menée in vitro et à l'aide de xénogreffes de cancer du sein triple négatif sur des modèles murins, cette étude analyse le rôle du récepteur ER bêta et des voies de signalisation induites par les cytochromes P450 dans la prolifération et la croissance des cellules cancéreuses
In the search for druggable targets to treat TNBC, ERβ, an estrogen receptor and tumor suppressor, has been suggested because it is found in 30% of TNBCs. In the present study, we found that except for SP1, the other tethering partners of ERβ (Fos, Jun, Fra1) are down-regulated in TNBC, meaning that the tumor-suppressive functions of ERβ are severely compromised. However, RNA seq revealed other driver pathways such as CYPs involved in the synthesis of fatty acid epoxides and in the inactivation of calcitriol and retinoic acid. Thus, ERβ agonists are unlikely to be useful in the treatment of TNBC. Instead, there is the danger that at estrogen response elements, ERβ may be acting as ERα does, and increase proliferation.To identify regulators of triple-negative breast cancer (TNBC), gene expression profiles of malignant parts of TNBC (mTNBC) and normal adjacent (nadj) parts of the same breasts have been compared. We are interested in the roles of estrogen receptor β (ERβ) and the cytochrome P450 family (CYPs) as drivers of TNBC. We examined by RNA sequencing the mTNBC and nadj parts of five women. We found more than a fivefold elevation in mTNBC of genes already known to be expressed in TNBC: BIRC5/survivin, Wnt-10A and -7B, matrix metalloproteinases (MMPs), chemokines, anterior gradient proteins, and lysophosphatidic acid receptor and the known basal characteristics of TNBC, sox10, ROPN1B, and Col9a3. There were two unexpected findings: 1) a strong induction of CYPs involved in activation of fatty acids (CYP4), and in inactivation of calcitriol (CYP24A1) and retinoic acid (CYP26A1); and 2) a marked down-regulation of FOS, FRA1, and JUN, known tethering partners of ERβ. ERβ is expressed in 20 to 30% of TNBCs and is being evaluated as a target for treating TNBC. We used ERβ+ TNBC patient-derived xenografts in mice and found that the ERβ agonist LY500703 had no effect on growth or proliferation. Expression of CYPs was confirmed by immunohistochemistry in formalin-fixed and paraffin-embedded (FFPE) TNBC. In TNBC cell lines, the CYP4Z1-catalyzed fatty acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) increased proliferation, while calcitriol decreased proliferation but only after inhibition of CYP24A1. We conclude that CYP-mediated pathways can be drivers of TNBC but that ERβ is unlikely to be a tumor suppressor because the absence of its main tethering partners renders ERβ functionless on genes involved in proliferation and inflammation.All study data are included in the article and/or SI Appendix.