title: A lipid-modified estrogen derivative that treats breast cancer independent of estrogen receptor expression through simultaneous induction of autophagy and apoptosis.
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.
authors.affiliation: Department of Biochemistry & Molecular Biology, Mayo Clinic, Guggenheim 1321, 200 First St. S.W., Rochester, MN 55905, USA.
authors.forename: Sutapa
authors.initials: S
authors.lastname: Sinha
authors.forename: Sayantani
authors.initials: S
authors.lastname: Roy
authors.forename: Bathula Surendar
authors.initials: BS
authors.lastname: Reddy
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Pal
authors.forename: Godeshala
authors.initials: G
authors.lastname: Sudhakar
authors.forename: Seethalakshmi
authors.initials: S
authors.lastname: Iyer
authors.forename: Shamit
authors.initials: S
authors.lastname: Dutta
authors.forename: Enfeng
authors.initials: E
authors.lastname: Wang
authors.forename: Pawan Kumar
authors.initials: PK
authors.lastname: Vohra
authors.forename: Karnati Rammohan
authors.initials: KR
authors.lastname: Roy
authors.forename: Pallu
authors.initials: P
authors.lastname: Reddanna
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D015197:Carcinogenicity Tests / Q000379:methods; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004967:Estrogens / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; D004967:Estrogens; D011960:Receptors, Estrogen; D058570:TOR Serine-Threonine Kinases