title: A potential estrogen mimetic effect of a bis(ethyl)polyamine analogue on estrogen receptor positive MCF-7 breast cancer cells.
abstract: BE-3-3-3-3 (1,15-(ethylamino)4,8,12-triazapentadecane) is a bis(ethyl)polyamine analogue under investigation as a therapeutic agent for breast cancer. Since estradiol (E(2)) is a critical regulatory molecule in the growth of breast cancer, we examined the effect of BE-3-3-3-3 on estrogen receptor α (ERα) positive MCF-7 cells in the presence and absence of E(2). In the presence of E(2), a concentration-dependent decrease in DNA synthesis was observed using [(3)H]-thymidine incorporation assay. In the absence of E(2), low concentrations (2.5-10 μM) of BE-3-3-3-3 increased [(3)H]-thymidine incorporation at 24 and 48 h. BE-3-3-3-3 induced the expression of early response genes, c-myc and c-fos, in the absence of E(2), but not in its presence, as determined by real-time quantitative polymerase chain reaction (qPCR). BE-3-3-3-3 had no significant effect on these genes in an ERα-negative cell line, MDA-MB-231. Chromatin immunoprecipitation assay demonstrated enhanced promoter occupation by either E(2) or BE-3-3-3-3 of an estrogen-responsive gene pS2/Tff1 by ERα and its co-activator, steroid receptor co-activator 3 (SRC-3). Confocal microscopy of BE-3-3-3-3-treated cells revealed membrane localization of ERα, similar to that induced by E(2). The failure of BE-3-3-3-3 to inhibit cell proliferation was associated with autophagic vacuole formation, and the induction of Beclin 1 and MAP LC3 II. These results indicate a differential effect of BE-3-3-3-3 on MCF-7 cells in the absence and presence of E(2), and suggest that pre-clinical and clinical development of polyamine analogues might require special precautions and selection of sensitive subpopulation of patients.
authors.affiliation: Department of Medicine and Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Nayvelt
authors.forename: Shali
authors.initials: S
authors.lastname: John
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Hsu
authors.forename: Pingar
authors.initials: P
authors.lastname: Yang
authors.forename: Wensheng
authors.initials: W
authors.lastname: Liu
authors.forename: Gokul
authors.initials: G
authors.lastname: Das
authors.forename: Mervi T
authors.initials: MT
authors.lastname: Hyvönen
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.forename: Tuomo A
authors.initials: TA
authors.lastname: Keinänen
authors.forename: Akira
authors.initials: A
authors.lastname: Shirahata
authors.forename: Rajesh
authors.initials: R
authors.lastname: Patel
authors.forename: Thresia
authors.initials: T
authors.lastname: Thomas
authors.forename: T J
authors.initials: TJ
authors.lastname: Thomas
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D006801:Humans; D018716:Molecular Mimicry; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D011073:Polyamines; D011960:Receptors, Estrogen