Effect of nonpersistent pesticides on estrogen receptor, androgen receptor, and aryl hydrocarbon receptor

Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. Methods: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. Results: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. Conclusion: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype.

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Cross-Talk in the Female Rat Mammary Gland: Influence of Aryl Hydrocarbon Receptor on Estrogen Receptor Signaling

Environmental Health Perspectives ◽

10.1289/ehp.1509680 ◽

2016 ◽

Vol 124 (5) ◽

pp. 601-610 ◽

Cited By ~ 12

Author(s):

Janina Helle ◽

Manuela I. Bader ◽

Annekathrin M. Keiler ◽

Oliver Zierau ◽

Günter Vollmer ◽

...

Keyword(s):

Estrogen Receptor ◽

Mammary Gland ◽

Aryl Hydrocarbon Receptor ◽

Cross Talk ◽

Female Rat ◽

Receptor Signaling ◽

Aryl Hydrocarbon ◽

Estrogen Receptor Signaling ◽

Rat Mammary Gland

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Reactivation of Estrogen Receptor α by Vorinostat Sensitizes Mesenchymal-Like Triple-Negative Breast Cancer to Aminoflavone, a Ligand of the Aryl Hydrocarbon Receptor

PLoS ONE ◽

10.1371/journal.pone.0074525 ◽

2013 ◽

Vol 8 (9) ◽

pp. e74525 ◽

Cited By ~ 24

Author(s):

Karri Stark ◽

Angelika Burger ◽

Jianmei Wu ◽

Phillip Shelton ◽

Lisa Polin ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Aryl Hydrocarbon Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Estrogen Receptor Α ◽

Aryl Hydrocarbon

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The Role of Aryl Hydrocarbon Receptor and Crosstalk with Estrogen Receptor in Response of Breast Cancer Cells to the Novel Antitumor Agents Benzothiazoles and Aminoflavone

International Journal of Breast Cancer ◽

10.4061/2011/923250 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 23

Author(s):

Mariana A. Callero ◽

Andrea I. Loaiza-Pérez

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Aryl Hydrocarbon Receptor ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Antitumor Agents ◽

Breast Cancers ◽

Nude Mouse Model ◽

Aryl Hydrocarbon ◽

Mcf 7

Many estrogen-receptor- (ER-) expressing breast cancers become refractory to ER-based therapies. New antitumor drugs like aminoflavone (AF) and benzothiazoles (Bzs) have been developed and have exquisite antitumor activity in ER+MCF-7 and T47D cells and in a MCF-7 nude mouse model. ER(−) breast cancer cells like MDA-MB-231 are less susceptible. We previously found in MCF-7 cells that these drugs activate the aryl hydrocarbon receptor (AhR) via translocation to the nucleus, induction of AhR-specific DNA binding activity, and expression of CYP1A1, whose transcription is controlled by the AhR-ARNT transcription factor. CYP1A1 metabolizes AF and Bz to a species which directly or after further metabolism damages DNA. In contrast an AhR-deficient variant of MCF-7 or cells with predominantly nuclear AhR expression, such as MDA-MB 231, are resistant. Thus, these drugs, unlike other neoplastic agents, require AhR-mediated signaling to cause DNA damage. This is a new treatment strategy for breast cancers with intact AhR signaling.

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