The estrogen receptor alpha‐derived peptide ERα17p (P₂₉₅‐T₃₁₁) exerts pro‐apoptotic actions in breast cancer cells in vitro and in vivo, independently from their ERα status

Abstract

In recent years, our knowledge on estrogen receptors (ER) has been modified profoundly with the identification and the deciphering of the role of its protein effectors, as well as with the deeper insight of its molecular structure/function dynamics, characteristics associated with its nucleo-cytoplasmic-membrane shuttling properties. Also, significant progress has been made concerning its turn-over and associated final proteasomal degradation processes.These advances could lead in the near future to the design and the synthesis of novel receptor-interacting drugs. Recently, a number of receptor-related peptides acting as specific ER ligands have been identified and extensively studied with respect to their estrogenic/antiestrogenic activities. Among them, ERa17p, a synthetic analog of the P 295 -T 311 sequence of ERa, has been shown to exert pseudo-estrogenic effects by interacting in the close vicinity of its hinge region (BF3 domain). Remarkably, this sequence appears as the epicenter of a number of post-transcriptional modifications as well as of the recruitment of co-regulators, suggesting that it would play a key role in ERa functions. Here, we provide evidence that ERa17p induces apoptosis in ERa-positive (MCF-7, T47D) and -negative (MDA-MB-231, SK-BR-3) breast cancer cells by an ERa-independent membrane mechanism, triggering major proapoptotic signaling cascades. Finally, ERa17p induces the regression of breast ERa-negative cancer tumor xenografts, without apparent toxicity, suggesting that it could represent a new attractive tool for the development of future promising therapeutic approaches, and providing a novel insight to ER regulation of cell fate.

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

“…In light of the previously reported activities displayed by ERa17p on cell proliferation and apoptosis [Gallo et al, 2007b;Pelekanou et al, 2011], we also found specific effects of the peptide on cell migration. Our data show two ERa-independent tendencies: In T47D (ERa þ ) and MDA-MB-231 (ERa À ) cells, ERa17p decreased and related pathways cannot be excluded.…”

“…In connection with its amphipathic character, ERa17p could associate to cell membranes to exert, at least partially, its actions [Pelekanou et al, 2011]. Indeed, we observed that a FITC-labeled peptide binds specifically (albeit weakly) to breast cancer cell membranes (Supplemental Fig.…”

“…Accordingly, a number of natural or modified peptide analogs have been synthesized and claimed to act as peptide estrogenrelated modulators (PERMs). ERa17p subscribes in this context, as: (i) it corresponds to a site of ERa, targeted by various posttranslational modifications [Gallo et al, 2007b], (ii) is subjected to conformational changes [Gallo et al, 2007b], (iii) interacts with calmodulin and Hsp70 [Gallo et al, 2008c], (iv) elicits pseudoestrogenic responses, under steroid starvation [Gallo et al, 2007b], (v) associates with ERa in vitro, at a site distinct from the hormonebinding pocket [Gallo et al, 2007b], (vi) interferes in vitro with the recruitment of p160 co-activator LxxLL binding motifs [Gallo et al, 2008c], and (vii) induces apoptosis (in vitro and in vivo) and xenograft tumor regression in animals [Pelekanou et al, 2011].…”

“…Recent investigation revealed a complementary involvement of ERa17p in breast cancer lines' apoptotic potential, under full (serum-supplemented) culture medium [Pelekanou et al, 2011]. Hence, one may hypothesize that ERa17p could elicit a large spectrum of cellular responses, by interfering with various signaling pathways, depending on the culture conditions.…”

Metabolomics and Transcriptional Responses in Estrogen Receptor Positive Breast Cancer Cells

“…This peptide also caused regression of ER-breast cancer tumor xenografts without apparent toxicity. This suggested a potentially new attractive tool for the development of promising therapeutic approaches, and also provided an insight to the cellular fate of ER (Pelekanou et al, 2011). The differences of the ER+ or ER-breast cancer not only relate to their morphology, but are also largely due to the differential metabolomics and differences in their transcriptional responses, which overall is a reflection of the selectivity of gene usage.…”