Effects of beta-carotene supplementation on molecular markers of lung carcinogenesis in male smokers.
Two primary prevention trials unexpectedly showed adverse effects of supplemental beta-carotene on lung cancer incidence in cigarette smokers. To elucidate the molecular mechanisms that might underlie these effects, we studied the immunohistochemical expression of cytochrome P450 1A1, 1A2, and 2E1, retinoic acid receptor beta, activated protein-1 elements, cyclin D1, and Ki67 in lung tumors and, when available, adjacent normal tissues obtained from incident cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Archival lung tissue was available from 52 men randomized to receive 20 mg of beta-carotene per day and 30 men randomized to the placebo arm, all of whom were diagnosed with incident non-small-cell lung carcinoma during the course of the trial and subsequently underwent radical pulmonary resection. In normal-appearing bronchial epithelium, positive staining for cyclin D1 was observed in 23% of cases in the beta-carotene group and 0% of cases in the placebo group (based on only 3 of 13 versus 0 of 11 cases staining positively, however; P = 0.04), with no differences in expression noted in lung tumor tissue (P = 0.48). There were no statistically significant differences in Ki67 expression in normal or cancerous lung tissue between intervention groups, although a small increase in staining in tumors was noted among cases in the beta-carotene versus placebo group (88% versus 71% of cases stained positive, respectively; P = 0.13). Contrary to expectation, beta-carotene supplementation had no apparent effect on retinoic acid receptor-beta expression. These findings suggest that male smokers supplemented with beta-carotene may have had an increased risk of lung cancer due to aberrant cell growth, although our results are based on a relatively small number of cases and require confirmation in other completed trials of beta-carotene supplementation.
Wright
Margaret E
ME
Department of Pathology, University of Illinois at Chicago, USA.
Groshong
Steve D
SD
Husgafvel-Pursiainen
Kirsti
K
Genova
Erin
E
Lucia
M Scott
MS
Wolff
Henrik
H
Virtamo
Jarmo
J
Albanes
Demetrius
D
D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000209:etiology* / Q000517:prevention & control; D003043:Cocarcinogenesis; D019938:Cyclin D1 / Q000032:analysis; D003580:Cytochromes / Q000032:analysis; D019587:Dietary Supplements / Q000009:adverse effects*; D004311:Double-Blind Method; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008168:Lung / Q000737:chemistry; D008175:Lung Neoplasms / Q000737:chemistry / Q000209:etiology* / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D009363:Neoplasm Proteins / Q000032:analysis*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D018168:Receptors, Retinoic Acid / Q000032:analysis; D012189:Retrospective Studies; D012907:Smoking / Q000009:adverse effects*; D024502:alpha-Tocopherol / Q000627:therapeutic use; D019207:beta Carotene / Q000009:adverse effects* / Q000627:therapeutic use
D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D003580:Cytochromes; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D019207:beta Carotene; D019938:Cyclin D1; D024502:alpha-Tocopherol