Abstract P5-09-14: Plant-derived estrogen receptorb agonists alone or in combination with aromatase inhibitors restore sensitivity in endocrine therapy resistant breast tumors

Autor: Rajeshwar Rao Tekmal, Ratna K. Vadlamudi, Naveen K. Krishnegowda, Cathy Samayoa
Rok vydání: 2013
Předmět:
Zdroj: Cancer Research. 73:P5-09
ISSN: 1538-7445
0008-5472
DOI: 10.1158/0008-5472.sabcs13-p5-09-14
Popis: Estrogen receptors (ER) play an important role in breast cancer. Over two-thirds of all breast cancers express ERa, and current endocrine therapies target its signaling. Antiestrogens (AE) block the binding of estrogen to ERα, while aromatase inhibitors (AI) inhibit local and systemic estrogen production. Both treatments improve outcomes for about 50% of patients with early or advanced ERα positive breast cancer. Unfortunately, therapeutic resistance frequently arises. There is a critical need to develop effective alternate strategies to prevent or delay the development of resistance to endocrine therapy and the resulting tumor progression. Both normal and tumor tissue express ERβ which has anti-proliferative activity and recent studies have identified several natural compounds that have the potential to function as ERβ agonists. Plant-derived ERβ-agonists, Liquiritigenin (Liq), from the plant Glycyrrhizae uralensis and S-equol, from the soy isoflavone daidzein, are currently in clinical trials for the treatment of vasomotor hot flashes associated with menopause. In this study we sought to determine if ERβ agonists alone or in combination with AI could resensitize Letrozole-resistant breast cancer cells in vivo. Xenografts were established using cells which model post-menopausal breast cancer. Endocrine therapy sensitive (MCF-7aro) and Letrozole resistant (LTLT-Ca) tumors were treated with either ERβ agonists or in combination with AI and progression was measured. In MCF-7aro tumors, ERβ agonist treatment reduced tumor volume and prolonged sensitivity to AI. In the therapy resistant tumors (LTLT-Ca), ERβ agonist treatment blocked tumor growth and restored sensitivity to AI therapy. To determine the molecular mechanism by which ERβ agonists inhibit tumor growth and prolong and restore sensitivity, qRT-PCR and western blot analysis was performed. Our results show changes in the levels of p53, NFkB, cyclin D1, and KLF5 in addition to other genes. To determine the role of ERβ agonists on the activation of these genes specific gene promoter-luciferase reporter constructs were used and the specificity of ERβ-mediated actions was confirmed using a siRNA approach. This study suggests that ERβ acts as a tumor suppressor by suppressing cell growth through the inhibition of cell cycle genes and by inducing apoptosis through the regulation of p53. In conclusion, this study demonstrates the potential role for ERβ agonists to improve adjuvant endocrine therapy to treat both hormone-responsive and hormone-resistant breast cancers. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-14.
Databáze: OpenAIRE
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