Estrogen receptor mediated cytochrome P450 enzyme regulation in breast cancer cell lines

Cancers in hormone-responsive tissues (e.g., the breast) occur at high incidence rates worldwide. Particularly in breast cancer (BC), the steroid hormone estrogen and alterations in its metabolism seem to play a significant role for an elevated risk of cancer development and progression. Estradiol was shown to regulate the expression and activity of cytochrome P450 (CYP) enzymes via the estrogen receptors α and β (ERα/ERβ). The enzymes CYP1B1 and CYP2B6 are involved in extrahepatic metabolism of estrogen. Both, the estrogen metabolite 4-hydroxyestradiol generated by CYP1B1, but also less active CYP2B6 polymorphisms are associated with increased BC risk. In addition, both enzymes are involved in extrahepatic drug metabolism and changes in activity could lead to BC therapy resistance against chemotherapeutic agents. In this study we addressed the ER mediated regulatory effects on CYP1B1 and 2B6 in BC cells on the transcriptional and enzymatic level. To determine a possible connection between altered CYP activity by estrogen and the poorer prognosis of ER negative BC, cells related to different BC subtypes were examined. qPCR measurements of the CYP expression after treatment with 17-β estradiol (E2) showed a significant induction of CYP1B1 in both ERα positive and negative cell lines. In contrast, CYP2B6 was linked to ERα and was only detectable in ER positive BC cell lines. While during E2 treatment of ERα positive cells, CYP2B6 mRNA was significantly reduced, previous E2 starvation resulted in a significant CYP2B6 induction by E2. This indicates, that permanently available E2 in culture medium leads to a change in ERα and β expression status, resulting in a different E2 mediated effect on CYP regulation. In the ER positive cell line T47D, an ERα mediated ERβ upregulation after E2 treatment was shown. That may explain the downregulation of CYP2B6 due to ERβ acting as an ERα antagonist. Taken together, this study provides evidence for ER mediated regulation of CYP1B1 and 2B6, which both are prognostically relevant for BC.