Inhibition of Neu-Induced Mammary Carcinogenesis in Transgenic Mice Expressing ERΔ3, a Dominant Negative Estrogen Receptor α Variant

The estrogen receptor ?? (ER??) splicing variant with an in-frame deletion of exon 3 (ER??3) is frequently expressed in the normal breast, but its influence on tumorigenesis has not been explored. In vitro, ER??3 has dominant negative activity, suggesting it may suppress estrogen stimulation in the breast. ER??3 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 ER??3 in all tissues examined, including the mammary gland. To investigate if ER??3 expression affects tumorigenesis, ER??3 mice were crossbred with MMTV-Neu mice. Mammary tumor onset was significantly delayed in ER??3/Neu versus MMTV-Neu females and metastatic incidence and burden was significantly reduced. Consequently, ER??3 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 ER??3 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 ER??3/Neu mice; however, metastatic progression was not inhibited in soy-treated ER??3/Neu mice, as it was in untreated ER??3/Neu mice. In contrast, tamoxifen (20?mg/1,800?kcal) significantly enhanced tumor prevention in ER??3/Neu versus MMTV-Neu mice (98?% vs. 81?% tumor free). The results in ER??3/Neu mice demonstrate that ER??3 influences estrogen-dependent mammary carcinogenesis and, thus, may be protective in women expressing ER??3 in the breast. However, exposure to different estrogens may augment or block its beneficial effects.