TCDD mediates inhibition of p53 and activation of ERα signaling in MCF-7 cells at moderate hypoxic conditions

Abstract

Abstract. TCDD (2,3,7, is known to promote cancer initiation and progression and accumulates in mammary fat tissue. Effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR). Physiological conditions of moderate hypoxia in breast cancer also activate another transcription factor, hypoxia-inducible factor-1 alpha (HIF-1·). In addition, the transcription factors p53 and the estrogen receptor alpha (ER·) are important key players in breast cancer progression. Here, human breast cancer cells cultured under mild hypoxic conditions were exposed to TCDD and analyzed for regulation of p53 signaling and ER· transactivation. Simultaneous exposure to TCDD and hypoxia resulted in a moderate but reproducible inhibition of p53 expression. Both the direct activation of the ER· and the transcriptional regulation of Hdm2 mediated this inhibition. As consequence the p53-mediated target gene expression (Dusp5) was reduced. Silencing of Dusp5 by simultaneous exposure of TCDD and hypoxia or by RNAi led to increased phosphorylation of ERK1/2. This increase resulted in transactivation of ER· and induction of ER·-mediated transcription of Hdm2 and SOCS3. Specificity of ER·-transactivation by ERK1/2 was confirmed by treatment with MAPKK-inhibitor PD98059. The combination of inhibition of functional p53 protein and induction of ER· signaling could serve as a model for the operational sequence of TCDD effects to prevent cell death and promote breast tumor progression.

State of the evidence 2017: an update on the connection between breast cancer and the environment

“…Administration of dioxins (especially TCDD) to pregnant rats leads to structural abnormalities in the development of their pups’ mammary tissues and higher incidence of tumors when the pups grow to adulthood [ 500 – 504 ]. TCDD may exert its cancer-causing effects both by decreasing the efficacy of tumor-suppressor mechanisms and by enhancing the estrogenic signaling within the mammary cells [ 505 ].…”

Aryl hydrocarbon receptor promotes hepatocellular carcinoma tumorigenesis by targeting intestine‐specific homeobox expression

“…Our previous clinical data and tumor cell analysis showed that high AHR expression was associated with low tumor suppressor protein (p53 and RB) expression but higher proto‐oncogene ( ISX, CCND1 , and E2F1 ) expression in vitro and in vivo . Although the detailed mechanisms underlying differential HCC prognostic outcomes remain unclear, AHR overexpression has been shown to inhibit p53 expression and activity in various cell lines and animal models, thereby contributing to tumor progression . Furthermore, AHR has been shown to interact with RB in various tumor cell lines, where it triggers E2F1 release and promotes cell cycle progression .…”

“…Despite the lack of evidence for DEN as an AHR ligand or AHR pathway metabolite, the chemical structure of DEN is homologous to polyromantic diphenyl ethers, the ligands of AHR. Although the actual role of AHR in tumorigenesis remains to be elucidated, the contribution of AHR to cancer progression or prevention may depend on the procarcinogen activation/detoxification balance and AHR expression in a cell‐specific manner . Further in‐depth research is needed to clarify this issue.…”

“…12,13 Although the detailed mechanisms underlying differential HCC prognostic outcomes remain unclear, AHR overexpression has been shown to inhibit p53 expression and activity in various cell lines and animal models, thereby contributing to tumor progression. 22,23 Furthermore, AHR has been shown to interact with RB in various tumor cell lines, where it triggers E2F1 release and promotes cell cycle progression. [24][25][26] AHR has been identified as an E2F1 coactivator that inhibits E2F1-induced apoptotic signaling and replaces it with cell proliferation signaling.…”

“…Although the actual role of AHR in tumorigenesis remains to be elucidated, the contribution of AHR to cancer progression or prevention may depend on the procarcinogen activation/detoxification balance and AHR expression in a cell-specific manner. 22 Further in-depth research is needed to clarify this issue. Nevertheless, data from previous publications and this study were used to generate a working tumorigenic hypothesis of the mechanism of AHR in HCC, as shown in Fig.…”