Tamoxifen Inhibition of Estrogen Receptor-α–Negative Mouse Mammary Tumorigenesis

Abstract

Tamoxifen reduces the relative risk of breast cancer developing from specific premalignant lesions. Many breast cancers that arise after tamoxifen treatment are estrogen receptor-alpha (ER-alpha)-negative, although premalignant lesions such as atypical ductal hyperplasia are highly ER-alpha-positive. The p53 null mouse mammary epithelial transplant model is characterized by ER-alpha-positive premalignant lesions that give rise to both ER-alpha-positive and ER-alpha-negative tumors. Given this progression from ER-alpha-positive to ER-alpha-negative lesions, we tested the ability of tamoxifen to block or delay mammary tumorigenesis in several versions of this model. In groups 1 and 2, p53 null normal mammary epithelial transplants were maintained in virgin mice. In groups 3 to 5, the p53 null and mammary transplants were maintained in mice continuously exposed to high levels of progesterone. In groups 6 and 7, transplants of the premalignant outgrowth line PN8a were maintained in virgin mice. Tamoxifen blocked estrogen signaling in these mice as evidenced by decreases in progesterone-induced lateral branching and epithelial proliferation in the mammary epithelium. Tamoxifen did not alter the elevated levels of progesterone in the blood while significantly reducing the circulating level of prolactin. Tamoxifen reduced tumor incidence in p53 null normal mammary epithelial transplants maintained in virgin mice from 55% to 5% and in progesterone-stimulated mice from 81% to 21%. The majority of the resultant tumors were ER-alpha-negative. Tamoxifen also significantly delayed tumorigenesis in the ER-alpha-positive high premalignant line PN8a from 100% to 75%. These results show that tamoxifen delays the emergence of ER-alpha-negative tumors if given early in premalignant progression.

PAK1 hyperactivation is sufficient for mammary gland tumor formation

“…We found that three out of eight (37.5%) tumors were ER and PR positive (Figures 4a and b) and that such tumors were benign adenomas and/or adenocarcinomas. Loss of ER in mouse models is known to correlate with a tumor's progression to malignancy (Medina et al, 2003); we also found that aggressive areas of squamous carcinomas showed no detectable immunostaining of ER or PR, suggesting that Pak1 hyperactivation plays a role in the development of hormone independence in some mammary gland tumors (Figure 4c, d, e and f).…”

“…However, most of the mammary gland animal models are estrogen receptor (ER) and progesterone receptor (PR) negative, with the exception of the p53 mouse model (Medina et al, 2003) and the murine mammary tumor virus-Wnt1 model (Bocchinfuso et al, 1999). Therefore, we next examined the status of ER and PR in Pak1-TG-induced tumors.…”

Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations

“…Loss of p53 does not inhibit the expression of ER in normal mammary cells, since ER is expressed in p53-null mammary epithelia (data not shown and Medina et al, 2003). Loss of p53 does not have a significant correlation with the ER status of human breast tumors, and 20% of tumors arising in mammary epithelia from p53-knockout mice express ER (Barbareschi et al, 1996;Medina et al, 2002).…”

Estrogen receptor-α expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice

“…Therefore, our proposed model, which emphasizes the significance of ER␣ signaling in the epithelium, might also suggest that tamoxifen has a direct effect on the growth of premalignant lesions in selected ER␣-positive murine mammary cancer models. Recent studies by Medina et al demonstrate that tamoxifen had a profound impact on the prevention of mammary tumorigenesis in the p53 knockout transplant model (20). The ER␣-expressing breast cancer models in combination with the ER␣ conditional knockout model will be invaluable for studying ER signaling in premalignant and cancerous lesions of the mammary gland.…”