ERα17p, an ERα P295-T311 fragment, modifies the migration of breast cancer cells, through actin cytoskeleton rearrangements

Abstract

Recently, our knowledge on estrogen receptor alpha (ERα) functions and fate has progressed: ERα enters in repeated transcription-modulating cycles (nucleus/cytoplasm/membrane trafficking processes and proteasomal degradation) that are governed by specific protein-protein interactions. Receptor fragments, especially those resulting from the proteolysis of its ligand binding domain, as well as corresponding synthetic peptides, have been studied with respect to their estrogenic/antiestrogenic potency. A peptide, corresponding to the human ERα P(295) -T(311) sequence (ERα17p) has been shown to alter breast cancer cell fate, triggering proliferation, or apoptosis. The aim of this work was to explore the effect of ERα17p on breast cancer cell migration and actin cytoskeleton dynamics and further analyze the mechanism of its membrane action. We show that ERα17p increases (MCF-7 and SK-BR-3 cells) or decreases (T47D and MDA-MB-231 cells) migration of breast cancer cells, in an ERα-independent manner, by mechanism(s) depending on Rho/ROCK and PI3K/Akt signaling pathways. Moreover, the peptide enhances the association of both estrogens and androgens to membranes and modifies cell migration, induced by E(2) -BSA. Additionally, initial evidence of a possible agonistic action of the peptide on GPR30 is also provided. ERα17p can be considered as a cell migration-modulator and could therefore constitute a therapeutic challenge, even in anti-estrogen-resistant tumors.

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

“…3B and 3C). In the wound repair/scratch assay, our data show that testosterone, as expected [49], increased the motility of T47D cells (Fig. 4A).…”

Whole transcriptome analysis of the ERα synthetic fragment P295‐T311 (ERα17p) identifies specific ERα‐isoform (ERα, ERα36)‐dependent and ‐independent actions in breast cancer cells

“…The number of modified transcripts was higher in ERα‐ and β‐expressing T47D and MDA‐MB‐231, than in ERα/β‐negative SKBR3 cells. There was a great analogy among the three cell lines concerning the number of common transcripts, modified in parallel by ERα17p and E 2 (75% in T47D and MDA‐MB‐231 cells, and 68% in SKBR3). Noticeably, only a very small number of transcripts (eight in T47D and MDA‐MB‐231 and none in SKBR3 cells) were modified in the opposite direction by E 2 and ERα17p, confirming at the transcription level the estrogenic nature of the peptide. The fact that 25–32% of ERα17p‐modified genes were different from those modified by E 2 could be relevant to the previously described ER‐independent actions of the peptide (Kampa et al., 2011; Pelekanou et al., 2011a). …”

“…On the contrary, in E 2 ‐containing medium, ERα17p induced apoptosis of breast cancer cells and regression of human breast cancer cell xenografts in mice (Pelekanou et al., 2011a). Moreover, it modified actin cytoskeleton dynamics and migration characteristics, implicated in the metastatic potential of breast tumors (Kampa et al., 2011). These latter actions occurred independently of the presence of ERα, suggesting the existence of an alternative (ER‐independent) mode of action of the peptide.…”

“…These latter actions occurred independently of the presence of ERα, suggesting the existence of an alternative (ER‐independent) mode of action of the peptide. Additionally, ERα17p associated with the plasma membrane and enhanced the binding of BSA‐conjugated (membrane‐impermeable) steroids, without directly competing with their membrane‐binding sites (Kampa et al., 2011; Pelekanou et al., 2011a). All these data concur to the concept that ERα17p is a multifaceted peptide regulator devoted to multiple actions in breast cancer cells.…”

From antimicrobial to anticancer peptides. A review

“…Increased apoptosis and decreased angiogenesis events are also reported with the antitumor effects. Other studies reveal the potential in using peptides that target or mimic hormonal receptors and hormonal-regulated genes for treating cancer (Leuschner et al, 2003; Leuschner and Hansel, 2005; Hansel et al, 2007; Kampa et al, 2011; Pelekanou et al, 2011; Byrne et al, 2012; Gao et al, 2013). Leuschner et al studied the ability of a series of compounds formed by synthetic membrane-disrupting peptides and a 15-amino acid residues segment of the beta chain of chorionic gonadotropin in targeting cells expressing luteinizing hormone/chorionic gonadotropin (LH/CG) receptors (Leuschner and Hansel, 2005; Hansel et al, 2007).…”