title: Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines.
abstract: There is a lack of understanding of the casual mechanisms behind the observation that some breast adenocarcinomas have identical morphology and comparatively different cellular growth behavior. This is exemplified by a differential response to radiation, chemotherapy, and other biological intervention therapies. Elevated concentrations of the free radical nitric oxide (NO), coupled with the up-regulated enzyme nitric oxide synthase (NOS) which produces NO, are activities which impact tumor growth. Previously, we adapted four human breast cancer cell lines: BT-20, Hs578T, T-47D, and MCF-7 to elevated concentrations of nitric oxide (or high NO [HNO]). This was accomplished by exposing the cell lines to increasing levels of an NO donor over time. Significantly, the HNO cell lines grew faster than did each respective ("PARENT") cell line even in the absence of NO donor-supplemented media. This was evident despite each "parent" being morphologically equivalent to the HNO adapted cell line. Herein, we characterize the HNO cells and their biological attributes against those of the parent cells. Pairs of HNO/parent cell lines were then analyzed using a number of key cellular activity criteria including: cell cycle distribution, DNA ploidy, response to DNA damage, UV radiation response, X-ray radiation response, and the expression of significant cellular enzymes. Other key enzyme activities studied were NOS, p53, and glutathione S-transferase-pi (GST-pi) expression. HNO cells were typified by a far more aggressive pattern of growth and resistance to various treatments than the corresponding parent cells. This was evidenced by a higher S-phase percentage, variable radioresistance, and up-regulated GST-pi and p53. Taken collectively, this data provides evidence that cancer cells subjected to HNO concentrations become resistant to free radicals such as NO via up-regulated cellular defense mechanisms, including p53 and GST-pi. The adaptation to NO may explain how tumor cells acquire a more aggressive tumor phenotype.
authors.affiliation: Center for Molecular Biology of Oral Diseases, University of Illinois at Chicago, College of Dentistry, 801 S. Paulina Street, Chicago, IL 60612, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Vesper
authors.forename: A
authors.initials: A
authors.lastname: Onul
authors.forename: G K
authors.initials: GK
authors.lastname: Haines
authors.forename: G
authors.initials: G
authors.lastname: Tarjan
authors.forename: J
authors.initials: J
authors.lastname: Xue
authors.forename: K M
authors.initials: KM
authors.lastname: Elseth
authors.forename: B
authors.initials: B
authors.lastname: Aydogan
authors.forename: M B
authors.initials: MB
authors.lastname: Altman
authors.forename: J C
authors.initials: JC
authors.lastname: Roeske
authors.forename: W A
authors.initials: WA
authors.lastname: Paradise
authors.forename: H
authors.initials: H
authors.lastname: De Vitto
authors.forename: J A
authors.initials: JA
authors.lastname: Radosevich
mesh_terms: D000222:Adaptation, Physiological; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051549:Glutathione S-Transferase pi / Q000096:biosynthesis; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D020030:Nitric Oxide Donors; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D051549:Glutathione S-Transferase pi