Molecular Mechanisms of Hormone Resistance of Breast Cancer

Abstract

More than 70% malignant mammary tumors contain steroid hormone receptors; this suggests the possibility of hormone therapy in the majority of patients with breast cancer (BC). The main cause of inefficiency of hormone therapy in BC is hormone resistance (tumor resistance to hormonal cytostatics). Here we discuss the main mechanisms of hormone resistance of BC and the mechanisms underlying the formation of hormone resistance of the tumors are analyzed at the molecular level. The data on the signal pathways of estrogen receptors (ER), the key regulators of BC cell proliferation, are presented. The most important factors of BC hormone resistance are: high activity/expression of receptor tyrosine kinases; high activity of proteins regulating cell defense mechanisms (Akt PI3K, mTOR); changes in the activities of cell cycle regulator proteins (Myc, c-Fos, Cyclin D1). Our experiments have demonstrated that estrogen-independent BC cell growth is supported by VEGF/VEGFR2 and EGF/EGFR mitogenic signal pathways. Our data indicate that NF-kappaB transcription factor is directly involved in the regulation of hormone-resistant BC cell growth and survival, while NF-kappaB suppression determines cell sensitivity to apoptotic activity of antitumor compounds. On the whole, the results indicate good prospects of using EGFR, HER-2/neu, mTOR, VEGFR, PI3K/Akt molecular pathways as targets for BC therapy, including therapy for BC resistant forms.