title: Indole-3-carbinol and its N-alkoxy derivatives preferentially target ERα-positive breast cancer cells.
abstract: Indole-3-carbinol (I3C) is a natural anti-carcinogenic compound found at high concentrations in Brassica vegetables. I3C was recently reported to inhibit neutrophil elastase (NE) activity, while consequently limiting the proteolytic processing of full length cyclin E into pro-tumorigenic low molecular weight cyclin E (LMW-E). In this study, we hypothesized that inhibition of NE activity and resultant LMW-E generation is critical to the anti-tumor effects of I3C. LMW-E was predominately expressed by ERα-negative breast cancer cell lines. However, ERα-positive cell lines demonstrated the greatest sensitivity to the anti-tumor effects of I3C and its more potent N-alkoxy derivatives. We found that I3C was incapable of inhibiting NE activity or the generation of LMW-E. Therefore, this pathway did not contribute to the anti-tumor activity of I3C. Gene expression analyzes identified ligand-activated aryl hydrocarbon receptor (AhR), which mediated sensitivity to the anti-tumor effects of I3C in ERα-positive MCF-7 cells. In this model system, the reactive oxygen species (ROS)-induced upregulation of ATF-3 and pro-apoptotic BH3-only proteins (e.g. NOXA) contributed to the sensitivity of ERα-positive breast cancer cells to the anti-tumor effects of I3C. Overexpression of ERα in MDA-MB-231 cells, which normally lack ERα expression, increased sensitivity to the anti-tumor effects of I3C, demonstrating a direct role for ERα in mediating the sensitivity of breast cancer cell lines to I3C. Our results suggest that ERα signaling amplified the pro-apoptotic effect of I3C-induced AhR signaling in luminal breast cancer cell lines, which was mediated in part through oxidative stress induced upregulation of ATF-3 and downstream BH3-only proteins.
authors.affiliation: a Department of Experimental Radiation Oncology ; University of Texas MD Anderson Cancer Center ; Houston , TX USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Caruso
authors.forename: Rody
authors.initials: R
authors.lastname: Campana
authors.forename: Caimiao
authors.initials: C
authors.lastname: Wei
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Su
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Hanks
authors.forename: William G
authors.initials: WG
authors.lastname: Bornmann
authors.forename: Khandan
authors.initials: K
authors.lastname: Keyomarsi
mesh_terms: D000438:Alcohols / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D019272:Leukocyte Elastase / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000438:Alcohols; D000970:Antineoplastic Agents; D019927:Cyclin E; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D007211:Indoles; D018336:Receptors, Aryl Hydrocarbon; C059688:alkoxyl radical; C016517:indole-3-carbinol; D019272:Leukocyte Elastase
keywords: AhR, aryl hydrocarbon receptor; CYP, cytochrome p450 oxidases; DIM, 3,3-diindoylmethane; ERα, estrogen receptor α; HMECs, human mammary epithelial cells; I3C, indole-3-carbinol; LMW-E, low molecular weight cyclin E; NE, neutrophil elastase; ROS, reactive oxygen species; RPPA, reverse phase protein array; TNBC, triple-receptor negative breast cancer; aryl hydrocarbon receptor; estrogen receptor α; indole-3-carbinol; neutrophil elastase