Sex-specific expression of gastrin-releasing peptide receptor: Relationship to smoking history and risk of lung cancer

Background: Activation of gastrin-releasing peptide receptor (GRPR) in huma n airways has been associated with a proliferative response of bronchial ce lls to gastrin-releasing peptide and with long-term tobacco use. The GRPR g ene is located on the X chromosome and escapes X-chromosome inactivation, w hich occurs in females, Increasing evidence demonstrates that women are mor e susceptible than men to tobacco carcinogenesis. We hypothesized that the susceptibility of women to the effects of tobacco may be associated with ai rway expression of GRPR. Methods: We analyzed GRPR messenger RNA (mRNA) exp ression in lung tissues and cultured airway cells from 78 individuals (40 m ales and 38 females) and in lung fibroblasts exposed to nicotine in vitro. Nicotinic acetylcholine receptors in airway cells were assayed by use of ra dioactively labeled nicotine and nicotine antagonists, A polymorphism in ex on 2 of the GRPR gene was used to detect allele-specific GRPR mRNA expressi on in some individuals, Statistical tests were two-sided. Results: GRPR mRN A expression was detected in airway cells and tissues of more female than m ale nonsmokers (55% versus 0%) and short-term smokers (1-25 pack-years [pac k-years number of packs of cigarettes smoked per day multiplied by the numb er of years of smoking]) (75% versus 20%) (P = .018 for nonsmoking and shor t-term smoking females versus nonsmoking and short-term smoking males), Fem ale smokers exhibited expression of GRPR mRNA at a lower mean pack-year exp osure than male smokers (37.4 pack-years versus 56.3 pack-years; P = .037), Lung fibroblasts and bronchial epithelial cells exhibited high-affinity, s aturable nicotinic acetylcholine-binding sites. Expression of GRPR mRNA in lung fibroblasts was elevated following exposure to nicotine, Conclusions: Our results suggest that the GRPR gene is expressed more frequently in wome n than in men in the absence of smoking and that expression of this gene is activated earlier in women in response to tobacco exposure, The presence o f two expressed copies of the GRPR gene in females may be a factor in the i ncreased susceptibility of women to tobacco-induced lung cancer.