Drivers and suppressors of triple-negative breast cancer

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 13 (ER13) 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 ER13. ER13 is expressed in 20 to 30% of TNBCs and is being evaluated as a target for treating TNBC. We used ER13+ TNBC patientderived xenografts in mice and found that the ER13 agonist LY500703 had no effect on growth or proliferation. Expression of CYPs was confirmed by immunohistochemistry in formalin-fixed and paraffinembedded (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 ER13 is unlikely to be a tumor suppressor because the absence of its main tethering partners renders ER13 functionless on genes involved in proliferation and inflammation.

Automated summary

Comparing gene expression profiles of malignant parts and normal adjacent parts of TNBC breasts revealed that CYP-mediated pathways may drive TNBC. However, despite being expressed in TNBC, ER13 is unlikely to be a tumor suppressor as its absence of main tethering partners renders it ineffective on genes related to proliferation and inflammation.