Endocrine Abstracts (2017) 50 OC6.5 | DOI: 10.1530/endoabs.50.OC6.5

Tumor immunosuppressive environment and tamoxifen resistance in rats exposed to EE2 in utero can be prevented with HDAC and DNMT inhibitors

Kerrie Bouker, Fabia De Oliveira Andrade & Leena Hil


Georgetown University, Washington, DC, USA.


Maternal exposures during pregnancy to endocrine disrupting chemicals increase daughter’s breast cancer risk in humans and animal models. We have previously found that these exposures also pre-program offspring’s mammary tumors to exhibit increased resistance to antiestrogen therapy, and that treatment with valproic acid (HDAC inhibitor) and hydralazine (DNMT inhibitor) prevented antiestrogen resistance. Here we investigated if maternal exposure to ethinyl estradiol (EE2) alters tumor immune environment in the offspring. Pregnant Sprague Dawley rats received 0 or 0.1 ppm EE2 via diet during gestation days 10–20. Estrogen receptor positive (ER+) mammary tumors in the offspring were induced with 9,12-dimethylbenz[a]anthracene, and when a tumor reached 13 mm in diameter, offspring were treated with 15 mg/kg tamoxifen (TAM), with or without 1.2 g/kg valproic acid and 5 mg/kg hydralazine. Before TAM treatment, mammary tumors in the EE2 offspring exhibited higher mRNA levels of Foxp3 (P=0.017), Tgfβ1 (P=0.075) and PD-L1 (P=0.013) than tumors in the control offspring. TAM treatment further upregulated Foxp3 (P=0.01) and Tgfβ1 (P<0.001) as well as PD-1 (P<0.001) in the EE2 offspring (compared with no TAM treated EE2 offspring). However, when in utero EE2 exposed rats received both TAM and valproic acid+hydralazine, mRNA levels of Foxp3 (P<0.001), Tgfβ1 (P=0.003), PD-L1 (P=0.011) and PD-1 (P<0.001) were significantly lower than in the EE2 offspring that were treated with TAM only. No changes were seen in the control offspring by TAM, with or without valproic acid+hydralazine treatment. Since elevated levels of Foxp3 and TGFβ1 are indicative of immunosuppression, and PD-L1 and its receptor PD-1 prevent cytotoxic T lymphocytes (CTLs) from killing cancer cells, our data suggest that in utero EE2 exposure promotes immunosuppressive tumor microenvironment that allows cancer cells to evade elimination by CTLs, and this effect is reversible by treatment with HDAC+DNMT inhibitors.

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