Johnston SR et al.Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer. J Steroid Biochem Mol Biol 106: 180-186

Department of Medicine, Royal Marsden Hospital, London SW3 6JJ, UK.
The Journal of Steroid Biochemistry and Molecular Biology (Impact Factor: 3.63). 08/2007; 106(1-5):180-6. DOI: 10.1016/j.jsbmb.2007.05.019
Source: PubMed


Improving endocrine responsiveness and preventing the development of resistance is the goal of many current strategies that are looking to combine aromatase inhibitors with novel drugs that target various pathways in estrogen receptor (ER) positive breast cancer. Pre-clinical models of acquired resistance to aromatase inhibitors have suggested an increase in several signaling pathways including peptide growth factor signaling (EGFR, HER2) and activation of the mTOR signaling pathway. These may result in associated 'cross-talk' activation of ER-dependent gene transcription, such that dual blockade of ER together with other signaling pathways has become a logical approach to improve endocrine responsivness. Clinical strategies with aromatase inhibitors are looking to prevent activation of these pathways either through combination with the selective ER downregulator fulvestrant, or with various signal transduction inhibitors (STIs) including monoclonal antibodies (trastuzumab), small molecule tyrosine kinase inhibitors (TKIs) against EGFR or HER2 (lapatinib, gefitinib) and mTOR antagonists (temsirolimus). Early clinical data have emerged this year for some of these approaches with mixed results. This article reviews the rationale for these strategies, and discusses the lessons that need to be learnt if we are to successfully integrate these new drugs with aromatase inhibitors in the clinic.

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    • "AIs are now first-line treatments for ER + breast cancer in post-menopausal women [6]. However, a significant percentage (range 30% to 65%) of patients either does not respond to AIs [7] or becomes resistant to them [8-10]. "
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    ABSTRACT: Although aromatase inhibitors (AIs; for example, letrozole) are highly effective in treating estrogen receptor positive (ER+) breast cancer, a significant percentage of patients either do not respond to AIs or become resistant to them. Previous studies suggest that acquired resistance to AIs involves a switch from dependence on ER signaling to dependence on growth factor-mediated pathways, such as human epidermal growth factor receptor-2 (HER2). However, the role of HER2, and the identity of other relevant factors that may be used as biomarkers or therapeutic targets remain unknown. This study investigated the potential role of transcription factor hypoxia inducible factor 1 (HIF-1) in acquired AI resistance, and its regulation by HER2. In vitro studies using AI (letrozole or exemestane)-resistant and AI-sensitive cells were conducted to investigate the regulation and role of HIF-1 in AI resistance. Western blot and RT-PCR analyses were conducted to compare protein and mRNA expression, respectively, of ERalpha, HER2, and HIF-1alpha (inducible HIF-1 subunit) in AI-resistant versus AI-sensitive cells. Similar expression analyses were also done, along with chromatin immunoprecipitation (ChIP), to identify previously known HIF-1 target genes, such as breast cancer resistance protein (BCRP), that may also play a role in AI resistance. Letrozole-resistant cells were treated with inhibitors to HER2, kinase pathways, and ERalpha to elucidate the regulation of HIF-1 and BCRP. Lastly, cells were treated with inhibitors or inducers of HIF-1alpha to determine its importance. Basal HIF-1alpha protein and BCRP mRNA and protein are higher in AI-resistant and HER2-transfected cells than in AI-sensitive, HER2- parental cells under nonhypoxic conditions. HIF-1alpha expression in AI-resistant cells is likely regulated by HER2 activated-phosphatidylinositide-3-kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, as its expression was inhibited by HER2 inhibitors and kinase pathway inhibitors. Inhibition or upregulation of HIF-1alpha affects breast cancer cell expression of BCRP; AI responsiveness; and expression of cancer stem cell characteristics, partially through BCRP. One of the mechanisms of AI resistance may be through regulation of nonhypoxic HIF-1 target genes, such as BCRP, implicated in chemoresistance. Thus, HIF-1 should be explored further for its potential as a biomarker of and therapeutic target.
    Breast cancer research: BCR 01/2014; 16(1):R15. DOI:10.1186/bcr3609 · 5.49 Impact Factor
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    • "With the increasing number of treatment options for breast cancer patients, therapeutic regimens are becoming more individualized. Pre-clinical data strongly support the rationale for combinatorial therapy (Johnston et al., 2007). However, while some clinical trials combining antiestrogens, EGFR/HER2 inhibitors, anti-angiogenics, and/or chemotherapies have yielded encouraging results (Romond et al., 2005; Polychronis et al., 2005; Tabernero, 2007), others have shown no benefit compared to monotherapy (Leary et al., 2007). "
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    ABSTRACT: The contributions of prolactin (PRL) to breast cancer are becoming increasingly recognized. To better understand the role for PRL in this disease, its interactions with other oncogenic growth factors and hormones must be characterized. Here, we review our current understanding of PRL crosstalk with other mammary oncogenic factors, including estrogen, epidermal growth factor (EGF) family members, and insulin-like growth factor-I (IGF-I). The ability of PRL to potentiate the actions of these targets of highly successful endocrine and molecular therapies suggests that PRL and/or its receptor (PRLR) may be an attractive therapeutic target(s). We discuss the potential benefit of PRL/PRLR-targeted therapy in combination with established therapies and implications for de novo and acquired resistance to treatment.
    Molecular and Cellular Endocrinology 09/2009; 307(1-2):1-7. DOI:10.1016/j.mce.2009.03.014 · 4.41 Impact Factor
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    ABSTRACT: Until recently, the study of nuclear receptor (NR) function in breast cancer biology has been largely limited to estrogen and progesterone receptors. The development of reliable gene expression arrays, real-time quantitative RT-PCR, and immunohistochemical techniques for studying NR superfamily members in primary human breast cancers has now revealed the presence and potential importance of several additional NRs in the biology of breast cancer. These include receptors for steroid hormones (including androgens and corticosteroids), fat-soluble vitamins A and D, fatty acids, and xenobiotic lipids derived from diet. It is now clear that after NR activation, both genomic and nongenomic NR pathways can coordinately activate growth factor signaling pathways. Advances in our understanding of both NR functional networks and epithelial cell growth factor signaling pathways have revealed a frequent interplay between NR and epithelial cell growth factor family signaling that is clinically relevant to breast cancer. Understanding how growth factor receptors and their downstream kinases are activated by NRs (and vice-versa) is a central goal for maximizing treatment opportunities in breast cancer. In addition to the estrogen receptor, it is predicted that modulating the activity of other NRs will soon provide novel prevention and treatment approaches for breast cancer patients.
    Molecular Endocrinology 05/2008; 22(10):2215-28. DOI:10.1210/me.2007-0421 · 4.02 Impact Factor
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