Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action

Abstract

Due to their favourable tolerability profiles, endocrine therapies have long been considered the treatment of choice for hormone-sensitive metastatic breast cancer. However, the oestrogen agonist effects of the available selective oestrogen receptor modulators, such as tamoxifen, and the development of cross-resistance between endocrine therapies with similar modes of action have led to the need for new treatments that act through different mechanisms. Fulvestrant (‘Faslodex’) is the first of a new type of endocrine treatment – an oestrogen receptor (ER) antagonist that downregulates the ER and has no agonist effects. This article provides an overview of the current understanding of ER signalling and illustrates the unique mode of action of fulvestrant. Preclinical and clinical study data are presented in support of the novel mechanism of action of this new type of ER antagonist.

Breast cancer cells can switch between estrogen receptor α and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance

“…Fulvestrant is a very potent antiestrogen that downregulates ERa protein expression and has no agonistic activity [4,50]. Fulvestrant resistance may be mediated through complete ERa repression, sometimes recognized as a loss of ERa expression and ERa independent activation of growth factor activity [4,51]. Our resistant cell lines display increased dependence on the ErbB pathway as evident from the increased sensitivity to the pan-ErbB inhibitor CI-1033 in the present study and to the EGFR inhibitor gefitinib in a previous study [11].…”

“…This is based on the observation that both our parental antiestrogen sensitive cells and the fulvestrant resistant cell lines had the ability to switch between ERa-and ErbB-mediated signaling, depending on externally applied factors. Fulvestrant is a very potent antiestrogen that downregulates ERa protein expression and has no agonistic activity [4,50]. Fulvestrant resistance may be mediated through complete ERa repression, sometimes recognized as a loss of ERa expression and ERa independent activation of growth factor activity [4,51].…”

“…After an initial response in the majority of patients, almost all patients with advanced disease develop resistance to the therapy. Treatment with the pure antiestrogen fulvestrant has proven effective upon progression on tamoxifen both in vitro and in vivo and is approved for second line endocrine treatment [1][2][3][4]. However, as for treatment with tamoxifen, development of resistance will inevitably occur.…”

A Novel Taspine Derivative, HMQ1611, Inhibits Breast Cancer Cell Growth via Estrogen Receptor α and EGF Receptor Signaling Pathways

“…The membrane ERa can also transactivate insulin-like growth factor 1 receptor (IGF-1R) and EGF receptor (EGFR)/HER2, which leads to the activation of the downstream extracellular signal-regulated kinases (ERK) signaling cascade (13)(14)(15). For ERapositive breast cancer, anti-ER treatment strategies involve selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators, and disruption of estrogen synthesis (16)(17)(18). However, the long-term anti-ER treatment results in drug resistance due to activation of HER2/EGFR growth factor receptor pathway (19)(20)(21).…”

Effect of phytoestrogens on basal and GnRH-induced gonadotropin secretion

“…Upon binding the ER, ICI prevents the receptor dimerization necessary for gene expression (Dauvois et al 1993, Osborne et al 2004. Furthermore, ICI effectively inactivates the ER by blocking the AF1 and AF2 transcription activation domains and ultimately increases ER degradation (Osborne et al 1995, Wakeling 1995.…”