Whole transcriptome analysis of the ER? synthetic fragment P295-T311 (ER?17p) identifies specific ER?-isoform (ER?, ER?36)-dependent and -independent actions in breast cancer cells.

ABSTRACT: ER?17p is a peptide corresponding to the sequence P295LMIKRSKKNSLALSLT311 of the estrogen receptor alpha (ER?) and initially found to interfere with ER?-related calmodulin binding. ER?17p was subsequently found to elicit estrogenic responses in E2-deprived ER?-positive breast cancer cells, increasing proliferation and ERE-dependent gene transcription. Surprisingly, in E2-supplemented media, ER?17p-induced apoptosis and modified the actin network, influencing cell motility. Here, we report that ER?17p internalizes in breast cancer cells (T47D, MDA-MB-231, SKBR3) and induces a massive early (3 h) transcriptional activity. Remarkably, about 75% of significantly modified transcripts were also modified by E2, confirming the pro-estrogenic profile of ER?17p. The different ER spectra of the used cell lines allowed us to identify a specific ER?17p signature related to ER? as well as its variant ER?36. With respect to ER?, the peptide activates nuclear (cell cycle, cell proliferation, nucleic acid and protein synthesis) and extranuclear signaling pathways. In contrast, through ER?36, it mainly triggers inhibitory actions on inflammation. This is the first work reporting a detailed ER?36-specific transcriptional signature. In addition, we report that ER?17p-induced transcripts related to apoptosis and actin modifying effects of the peptide are independent from its estrogen receptor(s)-related actions. We discuss our findings in view of the potential use of ER?17p as a selective peptidomimetic estrogen receptor modulator (PERM).

SUBMITTER: Notas G 

PROVIDER: S-EPMC5528475 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature