A lipid-modified estrogen derivative that treats breast cancer independent of estrogen receptor expression through simultaneous induction of autophagy and apoptosis.

Publication Type:

Journal Article

Source:

Molecular cancer research : MCR, Volume 9, Issue 3, p.364-74 (2011)

Keywords:

Animalsdigestive disease, digestive deseases Antineoplastic Agents, Hormonaldigestive disease, digestive deseases Apoptosisdigestive disease, digestive deseases Apoptosis Regulatory Proteinsdigestive disease, digestive deseases Autophagydigestive disease, digestive deseases Breast Neoplasmsdigestive disease, digestive deseases Carcinogenicity Testsdigestive disease, digestive deseases Carcinoma, Ductal, Breastdigestive disease, digestive deseases Cell Line, Tumordigestive disease, digestive deseases Cell Survivaldigestive disease, digestive deseases Estrogensdigestive disease, digestive deseases Femaledigestive disease, digestive deseases Humansdigestive disease, digestive deseases Maledigestive disease, digestive deseases Micedigestive disease, digestive deseases Mice, Inbred BALB Cdigestive disease, digestive deseases Ratsdigestive disease, digestive deseases Rats, Wistardigestive disease, digestive deseases Receptors, Estrogendigestive disease, digestive deseases TOR Serine-Threonine Kinases

Abstract:

It is a challenge to develop a universal single drug that can treat breast cancer at single- or multiple-stage complications, yet remains nontoxic to normal cells. The challenge is even greater when breast cancer-specific, estrogen-based drugs are being developed that cannot act against multistaged breast cancer complications owing to the cells differential estrogen receptor (ER) expression status and their possession of drug-resistant and metastatic phenotypes. We report here the development of a first cationic lipid-conjugated estrogenic derivative (ESC8) that kills breast cancer cells independent of their ER expression status. This ESC8 molecule apparently is nontoxic to normal breast epithelial cells, as well as to other noncancer cells. ESC8 induces apoptosis through an intrinsic pathway in ER-negative MDA-MB-231 cells. In addition, ESC8 treatment induces autophagy in these cells by interfering with the mTOR activity. This is the first example of an estrogen structure-based molecule that coinduces apoptosis and autophagy in breast cancer cells. Further in vivo study confirms the role of this molecule in tumor regression. Together, our results open new perspective of breast cancer chemotherapy through a single agent, which could provide the therapeutic benefit across all stages of breast cancer.