Mouse models of estrogen receptor-positive breast cancer

Abstract

Breast cancer is the most frequent malignancy and second leading cause of cancer-related deaths among women. Despite advances in genetic and biochemical analyses, the incidence of breast cancer and its associated mortality remain very high. About 60 - 70% of breast cancers are Estrogen Receptor alpha (ER-α) positive and are dependent on estrogen for growth. Selective estrogen receptor modulators (SERMs) have therefore provided an effective targeted therapy to treat ER-α positive breast cancer patients. Unfortunately, development of resistance to endocrine therapy is frequent and leads to cancer recurrence. Our understanding of molecular mechanisms involved in the development of ER-α positive tumors and their resistance to ER antagonists is currently limited due to lack of experimental models of ER-α positive breast cancer. In most mouse models of breast cancer, the tumors that form are typically ER-negative and independent of estrogen for their growth. However, in recent years more attention has been given to develop mouse models that develop different subtypes of breast cancers, including ER-positive tumors. In this review, we discuss the currently available mouse models that develop ER-α positive mammary tumors and their potential use to elucidate the molecular mechanisms of ER-α positive breast cancer development and endocrine resistance.

Keywords: Breast cancer; estrogen receptor-α; mouse models.

Figure 1

Estrogen functions through multiple pathways. Binding of Estrogen (E) to the Estrogen Receptor-α (ER-α) leads to translocation of the ligand receptor complex to the nucleus, where it affects transcription of an independent set of genes.[95] In addition, ER also exerts its effect on growth and proliferation of cells by binding to and affecting transactivation activity of various growth-related transcription factors (TF). Binding of the Wnt ligand to frizzled receptor leads to stabilization of β-catenin and its subsequent translocation to the nucleus, where it binds to TCF / LEF TF and drives its target genes. β-catenin activity in the nucleus is modulated by ER, leading to enhanced transactivation of the Wnt target genes.[96] Binding of estrogen to the membrane-bound ER activates downstream signaling pathways that include PI3K and Ras-MAPK pathways.[95] Transforming growth factor alpha (TGF-α) binds to its receptor, the epidermal growth factor receptor (EGFR), leading to its activation and a subsequent transcription of proliferative genes, through activation of PI3K and Ras-MAPK signaling.[21] Prolactin (PRL) binds to its trans-membrane cell-surface receptor, the prolactin receptor (PRLR), and triggers a tyrosine kinase-mediated signaling cascade, which leads to the activation of Stat1, Stat3, and Stat5, leading to their translocation to nucleus, where they bind to their target gene promoters.[97] ER binds to Stat target genes and enhances the transcriptional activity of Stats. Additionally, cyclin D1 binds directly to the hormone-binding domain of the estrogen receptor, resulting in an increased binding of the receptor to estrogen response element sequences, and upregulates ER-mediated transcription.[–99] Similarly, AIB1 in complex with Src1 and TIF2, potentiates transcription of ER-regulated genes.[100] Finally, ER has been shown to bind to p53 on the p53 target gene promoters in breast cancer cells, leading to repression of the p53 transactivation function.[–102]