title: Sensitization of epithelial growth factor receptors by nicotine exposure to promote breast cancer cell growth.
abstract: BACKGROUND
  Tobacco smoke is known to be the main cause of lung, head and neck tumors. Recently, evidence for an increasing breast cancer risk associated with tobacco smoke exposure has been emerging. We and other groups have shown that nicotine, as a non-conventional carcinogen, has the potential to facilitate cancer genesis and progression. However, the underlying mechanisms by which the smoke affects the breast, rather than the lung, remain unclear. Here, we examine possible downstream signaling pathways of the nicotinic acetylcholine receptor (nAChR) and their role in breast cancer promotion.
  
  
  METHODS
  Using human benign MCF10A and malignant MDA-MB-231 breast cells and specific inhibitors of possible downstream kinases, we identified nAChR effectors that were activated by treatment with nicotine. We further tested the effects of these effector pathways on the regulation of E2F1 activation, cell cycle progression and on Bcl-2 expression and long-term cell survival.
  
  
  RESULTS
  In this study, we demonstrated a novel signaling mechanism by which nicotine exposure activated Src to sensitize epidermal growth factor receptor (EGFR)-mediated pathways for breast cancer cell growth promotion. After the ligation of nAChR with nicotine, EGFR was shown to be activated and then internalized in both MCF10A and MDA-MB-231 breast cancer cells. Subsequently, Src, Akt and ERK1/2 were phosphorylated at different time points following nicotine treatment. We further demonstrated that through Src, the ligation of nicotine with nAChR stimulated the EGFR/ERK1/2 pathway for the activation of E2F1 and further cell progression. Our data also showed that Akt functioned directly downstream of Src and was responsible for the increase of Bcl-2 expression and long-term cell survival.
  
  
  CONCLUSIONS
  Our study reveals the existence of a potential, regulatory network governed by the interaction of nicotine and nAChR that integrates the conventional, mitogenic Src and EGFR signals for breast cancer development.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 00215, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishioka
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Luo
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.forename: Jinjin
authors.initials: J
authors.lastname: Guo
authors.forename: Chang Yan
authors.initials: CY
authors.lastname: Chen
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D002273:Carcinogens; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D011978:Receptors, Nicotinic; D009538:Nicotine; D066246:ErbB Receptors; D019061:src-Family Kinases
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