Abstract
Estrogen receptor alpha (ERα) and cyclin D1 are frequently co-expressed in human breast cancer. Some, but not all, studies link tamoxifen resistance to co-expression of cyclin D1 and ERα. In mice over-expression of either cyclin D1 or ERα in mammary epithelial cells is sufficient to induce mammary hyperplasia. Cyclin D1 over-expression in mice leads to mammary adenocarcinoma associated with activated estrogen signaling pathways. ERα over-expression in mice leads to mammary hyperplasia and cancer. Significantly, disease development in these mice is abrogated by loss of cyclin D1. Genetically engineered mouse models were used to determine whether or not ERα over-expression demonstrated cooperativity with cyclin D1 over-expression in cancer development, reaction to the chemical carcinogen DMBA, or tamoxifen response. Adding ERα over-expression to cyclin D1 over-expression increased the prevalence of hyperplasia but not cancer. Single dose DMBA exposure did not increase cancer prevalence in any of the genotypes although cyclin D1 over-expressing mice demonstrated a significant increase in hyperplasia. Tamoxifen treatment was initiated at both young and older ages to test for genotype-specific differences in response. Although normal ductal structures regressed in all genotypes at both younger and older ages, tamoxifen did not significantly reduce the prevalence of either hyperplasia or cancer in any of the genotypes. All of the cancers that developed were hormone receptor positive, including those that developed on tamoxifen, and all showed expression of nuclear-localized cyclin D1. In summary, development of tamoxifen resistant hyperplasia and cancer was associated with expression of ERα and cyclin D1. These preclinical models will be useful to test strategies for overcoming tamoxifen resistance, perhaps by simultaneously targeting cell cycle regulatory pathways associated with cyclin D1.
Highlights
Estrogen Receptor alpha (ERα) and cyclin D1 are frequently not invariably coexpressed in invasive human breast cancers [1,2,3,4,5]
Development of tamoxifen resistant hyperplasia and cancer was associated with expression of ERα and cyclin D1
The addition of ERα over-expression to cyclin D1 over-expression in the Conditional Estrogen Receptor in Mammary tissue (CERM)/D1 mice significantly increased the percentage of mice demonstrating one or more hyperplastic alveolar nodules (HANs) at one year of age (Fisher’s exact, one tailed test, p≤0.05); it did not increase the number of mice developing mammary adenocarcinoma (Figure 1A)
Summary
Estrogen Receptor alpha (ERα) and cyclin D1 are frequently not invariably coexpressed in invasive human breast cancers [1,2,3,4,5]. Cyclin D1 positively regulates progesterone receptor expression levels and this has been postulated to be a factor that contributes to the increased risk of cancer development following hormonal exposure [21]. Some studies have linked expression of cyclin D1 in ERα positive breast cancers to an impaired response to tamoxifen [22,23,24,25,26,27,28] while others show no statistically significant effects [29,30]. Estrogen receptor alpha (ERα) and cyclin D1 are frequently co-expressed in human breast cancer. Disease development in these mice is abrogated by loss of cyclin D1
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