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

Abstract

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.

When Good Turns Bad: Regulation of Invasion and Metastasis by ErbB2 Receptor Tyrosine Kinase

“…Loss of expression or function of several signaling molecules inhibits lung metastasis of mammary tumors in ErbB2/Neu overexpressing mice. These include protein tyrosine phosphatase 1B (PTP1B), adapter protein Gab2, EphA2 receptor tyrosine kinase, Rho GTPase activating protein p190B, receptor activator of nuclear factor- KB (RANK), estrogen receptor α, semaphorin receptor plexin-B1, and Rac specific guanidine nucleotide exchange factor DOCK1 [142,143,144,145,146,147,148,149], underlining the role of several signaling pathways in ErbB2-induced invasion and metastasis.…”

Rodent Models Assessing Mammary Tumor Prevention by Soy or Soy Isoflavones

“…Twenty-three studies were identified that evaluated mammary tumorigenesis following the administration of soy-based diets or purified isoflavones during postnatal development; fourteen using chemical carcinogens in rats [69,70,71,72,73,74,75,76,77,78,79,80,81,82] and nine using transgenic mice [83,84,85,86,87,88,89,90,91]. For this review, postnatal administration was defined by the initiation of soy-based diets or isoflavones at weaning or later and the design of these studies and the main findings are summarized in Table 1.…”

“…The findings were also highly variable in the transgenic mouse models with four of the nine studies showing at least some protective effect against mammary tumorigenesis (tumor incidence, latency, multiplicity or size) [83,86,87,88], with two of these studies observing a significant decrease in tumor incidence [83,88]. Three of the studies found no effect [84,89,91] and three of the studies found that soy isoflavones promoted at least one mammary tumor property [83,85,90]. The transgenic data was more difficult to evaluate as often other characteristics (i.e., high fat diet, estrogen levels) and different concentrations of isoflavones were assessed in the same study.…”

High levels of dietary soy decrease mammary tumor latency and increase incidence in MTB-IGFIR transgenic mice

“…This study found that soy significantly induced mammary tumor development in the low estrogen group, inhibited mammary tumor development in the high estrogen group and had no effect on the moderate estrogen group [ 27 ]. Another study using MMTV-erbB2 transgenics showed that initiating a soy diet at 2 months of age had no effect on mammary tumor development compared to a soy-free diet [ 28 ].…”