Drivers and suppressors of triple-negative breast cancer

Proc Natl Acad Sci U S A. 2021 Aug 17;118(33):e2104162118. doi: 10.1073/pnas.2104162118.

Abstract

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.

Keywords: breast cancer; cytochrome P450; estrogen receptor beta; fatty acid oxidation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphibian Proteins / genetics
  • Amphibian Proteins / metabolism
  • Animals
  • Benzopyrans / pharmacology
  • Calcitriol / pharmacology
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Down-Regulation
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism*
  • Fatty Acids / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Mice
  • Neoplasms, Experimental
  • Random Allocation
  • Survivin / genetics
  • Survivin / metabolism
  • Transcriptome
  • Tretinoin / pharmacology
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism

Substances

  • Amphibian Proteins
  • BIRC5 protein, human
  • Benzopyrans
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Fatty Acids
  • Survivin
  • Wnt Proteins
  • Wnt-10a protein, Pleurodeles waltl
  • erteberel
  • Tretinoin
  • Cytochrome P-450 Enzyme System
  • Calcitriol