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

Abstract

The majority (75%) of human breast cancers express estrogen receptor (ER). Although ER-positive tumors usually respond to antiestrogen therapies, 30% of them do not. It is not known what controls the ER status of breast cancers or their responsiveness to antihormone interventions. In this report, we document that transgenic (TG) expression of Wnt-1 in mice induces ER-positive tumors. Loss of Pten or gain of Ras mutations during the evolution of tumors in Wnt-1 TG mice has no effect on the expression of ER, but overexpression of Neu or loss of p53 leads to ER-negative tumors. Thus, our results provide compelling evidence that expression of ER in breast cancer may be influenced by specific genetic changes that promote cancer progression. These findings constitute a first step to explore the molecular mechanisms leading to ER-positive or ER-negative mammary tumors. In addition, we find that ER-positive tumors arising in Wnt-1 TG mice are refractory to both ovariectomy and the ER antagonist tamoxifen, but lose ER expression with tamoxifen, suggesting that antiestrogen selects for ERnegative tumor cells and that the ER-positive cell fraction is dispensable for growth of these tumors. This is a first report of a mouse model of antiestrogen-resistant ERpositive breast cancers, and could provide a powerful tool to study the molecular mechanisms that control antiestrogen resistance.

Met induces diverse mammary carcinomas in mice and is associated with human basal breast cancer

“…3 and Table S4). This result was unexpected given that genetically engineered mouse models commonly develop ER Ϫ mammary tumors (19). In addition, we observed that all Met mut tumors lacked PR expression.…”

Isolation and Molecular Characterization of Cancer Stem Cells in MMTV-Wnt-1 Murine Breast Tumors

“…The lower-than-expected frequency of engraftment from the Thy1ϩCD24ϩ cells could be due to damage to the cells during isolation that day. Alternatively, the secondary mutations leading to malignant transformation in that particular tumor could have resulted in a tumor whose tumorigenic cells were different from those driving the growth of the other tumors [31]. In six of seven tumors tested, the remaining tumor cells that were not-Thy1ϩCD24ϩCD45Ϫ were significantly depleted of cells capable of forming tumors.…”

“…Related to this, as MMTV-Wnt-1 tumors are classified as estrogen receptor (ER)-positive [31], and human ERϩ tumors have better prognosis than ERϪ tumors, we were interested to examine the distribution of ERϩ and ERϪ tumors within our two prognostic groups. As expected, the vast majority of the ERϪ patients fell within the worse prognosis group, as did patients with other poor prognostic markers such as basal cell subtype and poor histologic grade (Fig.…”

Estrogen receptor-positive mammary tumorigenesis in TGFα transgenic mice progresses with progesterone receptor loss

“…In combination with heterozygosity at the p53 locus, TGFa tumors were ERÀ, consistent with accelerated tumor progression facilitated by genomic instability or selective progression of a distinct tumor precursor subpopulation. Both ER þ and ERÀ tumors have been observed in other mouse models with one or more dysfunctional p53 alleles (Medina and Kittrell, 2003;Zhang et al, 2005).…”