This invention is situated in the field of medical applications, more specifically the diagnosis and treatment of cancers such as breast cancer, using a new diagnostic and therapeutic target peptide issued from the Estrogen Receptor alpha (ERα).
The present invention was built around the observation that a peptide issued from the breakdown of the ERα protein, containing regulatory sites of major importance, can be detected in the growth medium of the MCF-7 ERa-positive breast cancer cell line treated with estradiol. Interestingly, a synthetic peptide corresponding to the regulatory domain of this breakdown product displays a dual effect in breast cancer cells cultures, reminiscent of the behavior of partial anti-estrogens (SERMs): estrogen-like stimulating properties in absence of estradiol, apoptotic cell death when the hormone is not removed. Remarkably, this antitumor activity maintains in vivo: treatment of mammary tumors with this synthetic peptide significantly reduces their proliferation rate.
This present invention thus provides a new approach for diagnosing of ER alpha - positive breast cancers as well as a new modality for the treatment of the disease.
KEY ADVANTAGES OF THE TECHNOLOGY AND POTENTIAL APPLICATIONS
This new therapeutic approach will be suitable in the case of breast cancer resistances to classical anti-hormonal treatments. The polypeptide described here appears to be a valuable target for new treatments including immunotherapeutic strategies. Indeed, this polypeptide produced by hormone-dependent breast cancer cells when activated with estradiol, produces per se an increase of cell proliferation. Hence, targeting or blocking this polypeptide decreases breast cancer cells proliferation. Moreover, its administration under estrogen stimulation provokes tumors regression indicating a complementary therapeutic potency under such a condition.
For the diagnostic of estrogen receptor positive (ER- α –positive) breast cancers, detection of this peptide is a completely new approach. An immunoassay aimed to quantify its concentration in sera and tissue samples is under investigation.
MOST RELEVANT SCIENTIFIC PAPER
D. Gallo, I. Haddad, G. Laurent, J. Vihn, F. Jacquemotte, Y. Jacquot, G. Leclercq. “Regulatory function of the P295-T311 motif of the estrogen receptor alpha - does proteasomal degradation of the receptor induce emergence of peptides implicated in estrogenic responses?” Nucl. Recept. Signal. 2008, 6:e007.
D. Gallo et al. “Trophic effect in MCF-7 cells of ERalpha17p, a peptide corresponding to a platform regulatory motif of the estrogen receptor alpha--underlying mechanisms.” J. Steroid. Biochem. Mol. Biol. 2008, 109, 138-149. V. Pelekanou et al. “The estrogen receptor alpha-derived peptide ERα17p (P(295)-T(311)) exerts pro-apoptotic actions in breast cancer cells in vitro and in vivo, independently from their ERα status.” Mol. Oncol. 2011, 5, 36-47. M. Kampa et al. “ERα17p, an ERα P295 -T311 fragment, modifies the migration of breast cancer cells, through actin cytoskeleton rearrangements.” J. Cell Biochem. 2011, 112, 3786-96. C. Byrne et al. “ERα17p, a peptide reproducing the hinge region of the estrogen receptor α associates to biological membranes: A biophysical approach.” Steroids 2012, 77, 979-87. G. Notas et al. “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.” Mol. Oncol. 2013, 7, 595-610.
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Last Updated Sep 2014