Perfluorooctanoic acid (PFOA) as a stimulator of estrogen receptor-negative breast cancer MDA-MB-231 cell aggressiveness: Evidence for involvement of fatty acid 2-hydroxylase (FA2H) in the stimulated cell migration.

Abstract

Detailed in vitro studies on the effects of perfluorooctanoic acid (PFOA) have demonstrated that activation of peroxisome proliferator-activated receptor α (PPARα) is a key process by which PFOA affects the malignancy of estrogen receptor α (ERα)-positive breast cancer cells. However, there is very little information on the PPARα-regulated genes responsible for the effects of PFOA in ERα-negative breast cancer cell malignancy. We recently demonstrated that fatty acid 2-hydroxylase (FA2H) stimulates the migration of ERα-negative human MDA-MB-231 cells, and PPARα is a key factor for the induction of FA2H in these cells. However, evidence for the relationship between PFOA exposure and PPARα-FA2H axis-driven migration has not been obtained. Here we analyzed the effects of PFOA on PPARα transcription and FA2H expression in relation to MDA-MB-231 cell migration. We found that simultaneously with stimulated migration, PFOA upregulated FA2H and activated the transcription of PPARα. FA2H-selective siRNA, but not siRNA control, clearly dampened PFOA-mediated cell migration. There is an inhibitory interaction between PPARα and PPARβ/δ (i.e., PPARβ/δ can suppress PPARα-mediated transcription) in MDA-MB-231 cells, but even in the presence of PPARβ/δ expression, PFOA appeared to free PPARα to upregulate FA2H. Collectively, our findings show that i) PFOA activates PPARα-mediated transcription, ii) PFOA stimulates migration dependent on FA2H expression, and iii) mechanistically, PFOA relieves PPARβ/δ suppression of PPARα activity to upregulate FA2H in MDA-MB-231 cells.

• Authors: Genki Sakai, Masayo Hirao-Suzuki, Takayuki Koga, Takananobu Kobayashi, Jun Kamishikiryo, Michitaka Tanaka, Kiyonaga Fujii, Masufumi Takiguchi, Narumi Sugihara, Akihisa Toda, Shuso Takeda
• Journal: The Journal of toxicological sciences (J Toxicol Sci) Vol. 47 Issue 4 Pg. 159-168 ( 2022) ISSN: 1880-3989 [Electronic] Japan
• PMID: 35370244 (Publication Type: Journal Article)

Chemical References

• Caprylates
• Fluorocarbons
• Receptors, Estrogen
• perfluorooctanoic acid
• Mixed Function Oxygenases

Topics

• Caprylates (toxicity)
• Cell Movement
• Fluorocarbons
• Humans
• Mixed Function Oxygenases (genetics)
• Receptors, Estrogen
• Triple Negative Breast Neoplasms