Inhibition of Neu-induced mammary carcinogenesis in transgenic mice expressing ERΔ3, a dominant negative estrogen receptor α variant.

Davis, Vicki L

Shaikh, Firdos

Gallagher, Katie M

Villegas, Michael

Rea, Sheri L

Cline, J Mark

Hughes, Claude L

2018-06-04T19:44:36Z

2018-06-04T19:44:36Z

2012-12

2018-06-04T19:44:34Z

The estrogen receptor α (ERα) splicing variant with an in-frame deletion of exon 3 (ERΔ3) is frequently expressed in the normal breast, but its influence on tumorigenesis has not been explored. In vitro, ERΔ3 has dominant negative activity, suggesting it may suppress estrogen stimulation in the breast. ERΔ3 may inhibit classical signaling on estrogen response element (ERE)-regulated genes as well as activate non-classical pathways at Sp1 and AP-1 sites. Transgenic mice were developed that express mouse ERΔ3 in all tissues examined, including the mammary gland. To investigate if ERΔ3 expression affects tumorigenesis, ERΔ3 mice were crossbred with MMTV-Neu mice. Mammary tumor onset was significantly delayed in ERΔ3/Neu versus MMTV-Neu females and metastatic incidence and burden was significantly reduced. Consequently, ERΔ3 expression suppressed tumor development and metastasis in this aggressive model of HER2/Neu-positive breast cancer. To determine if ER ligands with anticancer activity may augment ERΔ3 protection, the bitransgenic mice were treated with tamoxifen and soy isoflavones starting at age 2 months. Soy protein with isoflavones (181 mg/1,800 kcal) did not affect tumor development in MMTV-Neu or ERΔ3/Neu mice; however, metastatic progression was not inhibited in soy-treated ERΔ3/Neu mice, as it was in untreated ERΔ3/Neu mice. In contrast, tamoxifen (20 mg/1,800 kcal) significantly enhanced tumor prevention in ERΔ3/Neu versus MMTV-Neu mice (98% vs. 81% tumor free). The results in ERΔ3/Neu mice demonstrate that ERΔ3 influences estrogen-dependent mammary carcinogenesis and, thus, may be protective in women expressing ERΔ3 in the breast. However, exposure to different estrogens may augment or block its beneficial effects.

1868-8497

1868-8500

https://hdl.handle.net/10161/17136

eng

Springer Science and Business Media LLC

Hormones & cancer

10.1007/s12672-012-0122-x

Animals

Mice, Transgenic

Humans

Mice

Mammary Tumor Virus, Mouse

Mammary Neoplasms, Experimental

Cell Transformation, Viral

Estrogen Receptor alpha

Immunohistochemistry

Genes, erbB-2

Female

Inhibition of Neu-induced mammary carcinogenesis in transgenic mice expressing ERΔ3, a dominant negative estrogen receptor α variant.

Journal article

Hughes, Claude L|0000-0001-5178-2258

5-6

School of Medicine

Duke

Obstetrics and Gynecology

Clinical Science Departments

Published

3