Nicotine Promotes Tumorigenesis in Mammary Tissues of Adolescent Rats

Abstract

Ninety percent of female smokers begin smoking during adolescence, the developmental period for maximal mammary tissue differentiation. We and others have demonstrated in vitro that nicotine – a primary component of tobacco and electronic cigarettes ‐ evokes premalignant and malignant changes in mammary epithelial cells via activation of intrinsic nicotinic receptors. Accordingly, the risk of developing breast cancer increases with initial age of regular smoking activity, an average of 8 years earlier in our clinical study of breast cancer patients who started smoking as adolescents. However, the effects of nicotine alone (absent smoke components) on breast tumor induction remains to be determined. Likewise, the effect of nicotine exposure during adolescence have yet to be evaluated for mammary tissue.The objective of this study was to determine whether nicotine enhances mammary tumorigenesis in female rats and whether these effects are more pronounced in adolescent relative to adult animals.Nicotine (2 mg/kg) or saline was delivered via osmotic minipumps to female adolescent (P22) and adult (P55) rats (n=6–8 per treatment group). Following administration of 1‐methyl‐nitrosourea (MNU, for induction of mammary tumors) or vehicle, tumor development was monitored for 16 weeks. Number, size, time of appearance and stage of tumors were evaluated.Tumors arose in both MNU‐induced and nicotine only treatment groups. Twenty‐two tumors arose in nicotine‐treated rats (n=45) that included both MNU‐, and notably, nicotine‐only treated adolescents (2 tumors). No tumors arose in animals treated exclusively with saline. Adolescent animals developed tumors 4–6 weeks earlier than their adult counterparts: in adolescents, tumors first appeared following 8 weeks of nicotine exposure, while the mean time for appearance in adults was after 14 weeks of nicotine treatment. Tumor volumes were 5 times larger in nicotine‐treated adolescent rats, while tumors of nicotine‐treated adults were ~2 times greater than their saline counterparts. Extensive vascularization characterized tumors from both nicotine‐treated adolescents and adults. Tumors exhibited primarily cribriform and papillary lesions, indicating that the lesional cells showed proliferative activities and the ability to form mass lesions, thereby mimicking human tumors. However, the potential of these tumor cells to develop into invasive carcinomas and to metastasize needs to be further elucidated.Our study demonstrates that nicotine can induce and enhance mammary tumorigenesis in vivo. This is the first report of nicotine alone inducing mammary tumors. Nicotine exposure resulted in earlier tumor onset and increased tumor volume in both saline and MNU‐induction models. Notably, these effects were more pronounced in adolescent than adult female rats. Therefore, the implications of this study are that nicotine exposure acquired during teenage smoking of tobacco or e‐cigarettes may exert pronounced, adverse influences on subsequent development of breast cancer in women.Support or Funding InformationSupport was provided by Department of Pediatrics Intramural Grant Program, Stony Brook Children's Hospital and Stony Brook University School of Medicine