C/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer

Xiao-Zheng Liu,Johanna Lepland,Man Hung Choi,Anders Molven,Stian Knappskog,Sina T Takle,Per E Lønning,Noelly Madeleine,Anastasiia Rulina,Stacey D’Mello Peters,Nils Halberg,Line Pedersen,James B Lorens,Hani Goodarzi,Cara Ellen Wogsland,Sturla Magnus Grøndal

doi:10.1038/s41467-021-27734-2

Abstract

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network.

Highlights

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer
High-fat diet (HFD) feeding resulted in weight gain, and HFD-fed mice displayed multiple hallmarks of obesityinduced comorbidities such as liver steatosis, hyperinsulinemia, hyperglycemia, and reduced glucose clearance compared to the regular chow diet-fed mice (Fig. S1A–D)
Following mammary fat pad implantation of limiting numbers of E0771 and TeLi cells, we demonstrate that high-fat environments consistently promote tumor formation with a 6–10-fold enrichment in cancer stem cell frequencies (Fig. 1a)

Summary

Introduction

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/ enhancer-binding protein beta (C/EBPB). We show that cellular adaptation to obese environments is phenotypically and mechanistically recapitulated by long-term exposure to high concentrations of palmitic acid (PA) in vitro Both obesity and long-term adaptation to high levels of PA engender cancer cell dedifferentiation towards stem cell-like properties in both human biobank material and mouse models. We identify epigenetic activation of the CCAAT/ enhancer-binding protein beta (C/EBPB) transcription factor as a required regulator of obesity-induced cancer stem-like properties. Our findings demonstrate that cellular adaptation to obesityinduced PA is a key driver of tumor initiation in PM/ER−/PR− breast cancer cells in obesity

Objectives

Methods

Results

Conclusion