Abstract
Estradiol (E2) and the oestrogen receptor-alpha (ERα) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ERα signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ERα activity-regulator synthetic peptide (ERAP: 165–177 amino acids), derived from α-helical BIG3 sequence, resulted in a significant anti-tumour effect. However, the duration of this effect was very short for viable clinical application. We developed the chemically modified ERAP using stapling methods (stapledERAP) to improve the duration of its antitumour effects. The stapledERAP specifically inhibited the BIG3-PHB2 interaction and exhibited long-lasting suppressive activity. Its intracellular localization without the membrane-permeable polyarginine sequence was possible via the formation of a stable α-helix structure by stapling. Tumour bearing-mice treated daily or weekly with stapledERAP effectively prevented the BIG3-PHB2 interaction, leading to complete regression of E2-dependent tumours in vivo. Most importantly, combination of stapledERAP with tamoxifen, fulvestrant, and everolimus caused synergistic inhibitory effects on growth of breast cancer cells. Our findings suggested that the stapled ERAP may be a promising anti-tumour drug to suppress luminal-type breast cancer growth.
Highlights
Breast cancer is the most common cancer among women, and its incidence is rising worldwide
We synthesized a series of stapled α-helices of ER α activity-regulator synthetic peptide (ERAP) bearing the olefin scaffold (Fig. 1a)
We confirmed that stapled ERAP (stERAP)-2 significantly suppressed the E2-induced expression of the ERα-target genes TFF1 and CCND1 for 96 h treatment (Supplementary Fig. S1e). These findings suggested that the high α-helical content of stERAP-2 enhanced proteolytic stability, which may be strongly correlated with sustained suppression of breast cancer cell growth
Summary
Breast cancer is the most common cancer among women, and its incidence is rising worldwide. (prohibitin 2) in the cytoplasm, thereby inhibiting E2-dependent translocation to the nucleus and plasma membrane This interaction results in the constitutive activation of the E2/ERα signalling pathway in breast cancer cells[9]. In the present study, stapled ERAP (stERAP), possessing stabilized α-helices, sustained inhibition of the BIG3-PHB2 interaction, thereby suppressing constitutive ERα activation in breast cancer cells. StERAP caused complete regression of E2-dependent tumour formation without any detectable toxicity in murine xenografts These findings suggest that hydrocarbon stapling of ERAP may provide an effective therapeutic strategy to modulate the BIG3-PHB2 interaction in E2-dependent breast cancer cells and may be a viable means to overcome endocrine resistance
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