Long-term exposure to extremely low-dose of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induce non-malignant breast epithelial cell transformation through activation of the a9-nicotinic acetylcholine receptor-mediated signaling pathway

A.-F.S. Fararjeh, S.-H. Tu, L.-C. Chen, T.-C. Cheng, Y.-R. Liu, H.-L. Chang, H.-W. Chang, C.-C. Huang, H.-C.R. Wang, W.W. Hwang-Verslues, C.-H. Wu, Y.-S. Ho

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Abstract

Breast cancer (BC) is the most common cancer affecting women worldwide and has been associated with active tobacco smoking. Low levels of nicotine (Nic) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been detected in cases of second-hand smoke (SHS). However, the correlation between SHS and BC risk remains controversial. In this study, we investigated whether the physiological SHS achievable dose of Nic and tobacco specific nitrosamine, NNK act together to induce breast carcinogenesis using an in vitro breast cell carcinogenesis model. Immortalized non-tumorigenic breast epithelial cell line, HBL-100 used for a time-course assay, was exposed to very low levels of either Nic or NNK, or both. The time-course assay consisted of 23 cycles of nitrosamines treatment. In each cycle, HBL-100 cells were exposed to 1pM of Nic and/or 100 femtM of NNK for 48 hours. Cells were passaged every 3 days and harvested after 10, 15, and 23 cycles. Our results demonstrated that the tumorigenicity of HBL-100, defined by soft agar colony forming, proliferation, migration and invasion abilities, was enhanced by co-exposure to physiologically SHS achievable doses of Nic and NNK. In addition, α9-nAChR signaling activation, which plays an important role in cellular proliferation and cell survival, was also observed. Importantly, an increase in stemness properties including the prevalence of CD44+/CD24− cells, increase Nanog expression and mammosphere-forming ability were also observed. Our results indicate that chronic and long term exposure to environmental tobacco smoke, may induce breast cell carcinogenesis even at extremely low doses. © 2018 Wiley Periodicals, Inc.
Original languageEnglish
JournalEnvironmental Toxicology
DOIs
Publication statusPublished - 2018

Fingerprint

Nicotinic Receptors
Nicotine
Tobacco Smoke Pollution
Smoke
smoke
Breast
Epithelial Cells
Chemical activation
Tobacco
Nitrosamines
tobacco
Carcinogenesis
Aptitude
cancer
assay
Assays
Breast Neoplasms
smoking
agar
Environmental Exposure

Keywords

  • breast cancer
  • carcinogenesis
  • nicotine
  • NNK
  • second-hand smoke
  • Cell culture
  • Cell proliferation
  • Cells
  • Chemical activation
  • Diseases
  • Ketones
  • Nicotine
  • Pathology
  • Physiological models
  • Physiology
  • Smoke
  • Tissue culture
  • Tobacco
  • Breast Cancer
  • Carcinogenesis models
  • Cellular proliferations
  • Environmental tobacco smokes
  • Nicotinic acetylcholine receptors
  • Second hand smokes
  • Tobacco specific nitrosamines
  • Cell signaling

Cite this

@article{ca28837df2cf47b0be763cf0eed196d4,
title = "Long-term exposure to extremely low-dose of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induce non-malignant breast epithelial cell transformation through activation of the a9-nicotinic acetylcholine receptor-mediated signaling pathway",
abstract = "Breast cancer (BC) is the most common cancer affecting women worldwide and has been associated with active tobacco smoking. Low levels of nicotine (Nic) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been detected in cases of second-hand smoke (SHS). However, the correlation between SHS and BC risk remains controversial. In this study, we investigated whether the physiological SHS achievable dose of Nic and tobacco specific nitrosamine, NNK act together to induce breast carcinogenesis using an in vitro breast cell carcinogenesis model. Immortalized non-tumorigenic breast epithelial cell line, HBL-100 used for a time-course assay, was exposed to very low levels of either Nic or NNK, or both. The time-course assay consisted of 23 cycles of nitrosamines treatment. In each cycle, HBL-100 cells were exposed to 1pM of Nic and/or 100 femtM of NNK for 48 hours. Cells were passaged every 3 days and harvested after 10, 15, and 23 cycles. Our results demonstrated that the tumorigenicity of HBL-100, defined by soft agar colony forming, proliferation, migration and invasion abilities, was enhanced by co-exposure to physiologically SHS achievable doses of Nic and NNK. In addition, α9-nAChR signaling activation, which plays an important role in cellular proliferation and cell survival, was also observed. Importantly, an increase in stemness properties including the prevalence of CD44+/CD24− cells, increase Nanog expression and mammosphere-forming ability were also observed. Our results indicate that chronic and long term exposure to environmental tobacco smoke, may induce breast cell carcinogenesis even at extremely low doses. {\circledC} 2018 Wiley Periodicals, Inc.",
keywords = "breast cancer, carcinogenesis, nicotine, NNK, second-hand smoke, Cell culture, Cell proliferation, Cells, Chemical activation, Diseases, Ketones, Nicotine, Pathology, Physiological models, Physiology, Smoke, Tissue culture, Tobacco, Breast Cancer, Carcinogenesis models, Cellular proliferations, Environmental tobacco smokes, Nicotinic acetylcholine receptors, Second hand smokes, Tobacco specific nitrosamines, Cell signaling",
author = "A.-F.S. Fararjeh and S.-H. Tu and L.-C. Chen and T.-C. Cheng and Y.-R. Liu and H.-L. Chang and H.-W. Chang and C.-C. Huang and H.-C.R. Wang and W.W. Hwang-Verslues and C.-H. Wu and Y.-S. Ho",
note = "Export Date: 17 October 2018 Article in Press CODEN: ETOXF Correspondence Address: Ho, Y.-S.; TMU Research Center of cancer Translational Medicine, Taipei Medical UniversityTaiwan; email: hoyuansn@tmu.edu.tw References: DeSantis, C.E., Ma, J., Goding Sauer, A., Newman, L.A., Jemal, A., Breast cancer statistics, 2017, racial disparity in mortality by state (2017) CA Cancer J Clin, 67 (6), pp. 439-448; Collins, A., Politopoulos, I., The genetics of breast cancer: risk factors for disease (2011) Appl Clin Genet, 4, pp. 11-19; Balekouzou, A., Yin, P., Pamatika, C.M., Reproductive risk factors associated with breast cancer in women in Bangui: a case-control study (2017) BMC Womens Health, 17 (1), p. 14; Hiatt, R.A., Brody, J.G., Environmental determinants of breast cancer (2018) Annu Rev Public Health; Kycler, W., Kubiak, A., Rzymski, P., Impact of selected environmental factors on attendance in the breast and cervical cancer early detection Programme in the Wielkopolska Province of Poland during 2007-2012 (2017) Ann Agric Environ Med, 24 (3), pp. 467-471; Andersen, Z.J., Stafoggia, M., Weinmayr, G., Long-term exposure to ambient air pollution and incidence of postmenopausal breast cancer in 15 European cohorts within the ESCAPE project (2017) Environ Health Perspect, 125 (10), p. 107005; Kaplanis, J., Gordon, A., Shor, T., Quantitative analysis of population-scale family trees with millions of relatives (2018) Science, 360 (6385). , 171–175; Majeed, W., Aslam, B., Javed, I., Breast cancer: major risk factors and recent developments in treatment (2014) Asian Pac J Cancer Prev, 15 (8), pp. 3353-3358; Macacu, A., Autier, P., Boniol, M., Boyle, P., Active and passive smoking and risk of breast cancer: a meta-analysis (2015) Breast Cancer Res Treat, 154 (2), pp. 213-224; Chen, C., Huang, Y.B., Liu, X.O., Active and passive smoking with breast cancer risk for Chinese females: a systematic review and meta-analysis (2014) Chin J Cancer, 33 (6), pp. 306-316; Luo, J., Margolis, K.L., Wactawski-Wende, J., Association of active and passive smoking with risk of breast cancer among postmenopausal women: a prospective cohort study (2011) BMJ, 342, p. d1016; Glantz, S.A., Johnson, K.C., The surgeon general report on smoking and health 50 years later: breast cancer and the cost of increasing caution (2014) Cancer Epidemiol Biomarkers Prev, 23 (1), pp. 37-46; Warren, G.W., Alberg, A.J., Kraft, A.S., Cummings, K.M., The 2014 surgeon General's report: {"}the health consequences of Smoking-50 years of Progress{"} a paradigm shift in cancer care (2014) Cancer, 120 (13), pp. 1914-1916; Lee, C.H., Huang, C.S., Chen, C.S., Overexpression and activation of the alpha9-nicotinic receptor during tumorigenesis in human breast epithelial cells (2010) J Natl Cancer Inst, 102 (17), pp. 1322-1335; Wei, P.L., Kuo, L.J., Huang, M.T., Nicotine enhances colon cancer cell migration by induction of fibronectin (2011) Ann Surg Oncol, 18 (6), pp. 1782-1790; Lien, Y.C., Wang, W., Kuo, L.J., Nicotine promotes cell migration through Alpha7 nicotinic acetylcholine receptor in gastric cancer cells (2011) Ann Surg Oncol, 18 (9), pp. 2671-2679; Shih, Y.L., Liu, H.C., Chen, C.S., Combination treatment with Luteolin and quercetin enhances Antiproliferative effects in nicotine-treated MDA-MB-231 cells by Down-regulating nicotinic acetylcholine receptors (2010) J Agr Food Chem, 58 (1), pp. 235-241; Lee, C.H., Chang, Y.C., Chen, C.S., Crosstalk between nicotine and estrogen-induced estrogen receptor activation induces alpha9-nicotinic acetylcholine receptor expression in human breast cancer cells (2011) Breast Cancer Res Treat, 129 (2), pp. 331-345; Chen, C.S., Lee, C.H., Hsieh, C.D., Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins (2011) Breast Cancer Res Treat, 125 (1), pp. 73-87; Tu, S.H., Ku, C.Y., Ho, C.T., Tea polyphenol (−)-epigallocatechin-3-gallate inhibits nicotine- and estrogen-induced alpha9-nicotinic acetylcholine receptor upregulation in human breast cancer cells (2011) Mol Nutr Food Res, 55 (3), pp. 455-466; Avila-Tang, E., Al-Delaimy, W.K., Ashley, D.L., Assessing secondhand smoke using biological markers (2013) Tob Control, 22 (3), pp. 164-171; Florek, E., Piekoszewski, W., Basior, A., Effect of maternal tobacco smoking or exposure to second-hand smoke on the levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in urine of mother and the first urine of newborn (2011) J Physiol Pharmacol, 62 (3), pp. 377-383; Ho, Y.S., Chen, C.H., Wang, Y.J., Tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFkappaB activation and cyclin D1 up-regulation (2005) Toxicol Appl Pharmacol, 205 (2), pp. 133-148; Wei, P.L., Chang, Y.J., Ho, Y.S., Tobacco-specific carcinogen enhances colon cancer cell migration through Alpha7-nicotinic acetylcholine receptor (vol 249, pg 978, 2009) (2009) Ann Surg, 250 (6), p. 1046; Wang, W., Chin-Sheng, H., Kuo, L.J., NNK enhances cell migration through alpha 7-nicotinic acetylcholine receptor accompanied by increased of fibronectin expression in gastric cancer (2012) Ann Surg Oncol, 19, pp. S580-S588; Song, X., Siriwardhana, N., Rathore, K., Lin, D., Wang, H.C., Grape seed proanthocyanidin suppression of breast cell carcinogenesis induced by chronic exposure to combined 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo [a]pyrene (2010) Mol Carcinog, 49 (5), pp. 450-463; Gray, J.M., Rasanayagam, S., Engel, C., Rizzo, J., State of the evidence 2017: an update on the connection between breast cancer and the environment (2017) Environmental Health, 16 (1). , 94; Ricciardiello, L., Ahnen, D.J., Lynch, P.M., Chemoprevention of hereditary colon cancers: time for new strategies (2016) Nat Rev Gastro Hepat, 13 (6), pp. 352-361; Choudhary, S., Sood, S., Donnell, R.L., Wang, H.C., Intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (2012) Carcinogenesis, 33 (4), pp. 876-885; Chen, P., Duan, X., Li, M., Systematic network assessment of the carcinogenic activities of cadmium (2016) Toxicol Appl Pharmacol, 310, pp. 150-158; Wu, K.H., Ho, C.T., Chen, Z.F., The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter (2018) J Food Drug Anal, 26 (1), pp. 221-231; Hanahan, D., Weinberg, R.A., Hallmarks of cancer: the next generation (2011) Cell, 144 (5), pp. 646-674; Mennecier, G., Torres, L.N., Cogliati, B., Chronic exposure of lung alveolar epithelial type II cells to tobacco-specific carcinogen NNK results in malignant transformation: a new in vitro lung carcinogenesis model (2014) Mol Carcinog, 53 (5), pp. 392-402; Jandial, R., (2013) Metastatic cancer : clinical and biological perspectives., , Austin, Texas, USA, Landes Bioscience; Rathore, K., Wang, H.C.R., Mesenchymal and stem-like cell properties targeted in suppression of chronically-induced breast cell carcinogenesis (2013) Cancer Lett, 333 (1), pp. 113-123; Mi, K., Xing, Z., CD44(+)/CD24(−) breast cancer cells exhibit phenotypic reversion in three-dimensional self-assembling peptide RADA16 nanofiber scaffold (2015) Int J Nanomed, 10, pp. 3043-3053; Sheridan, C., Kishimoto, H., Fuchs, R.K., CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis (2006) Breast Cancer Res, 8 (5), p. 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year = "2018",
doi = "10.1002/tox.22659",
language = "English",
journal = "Environmental Toxicology",
issn = "1520-4081",
publisher = "John Wiley and Sons Inc.",

}

TY - JOUR

T1 - Long-term exposure to extremely low-dose of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induce non-malignant breast epithelial cell transformation through activation of the a9-nicotinic acetylcholine receptor-mediated signaling pathway

AU - Fararjeh, A.-F.S.

AU - Tu, S.-H.

AU - Chen, L.-C.

AU - Cheng, T.-C.

AU - Liu, Y.-R.

AU - Chang, H.-L.

AU - Chang, H.-W.

AU - Huang, C.-C.

AU - Wang, H.-C.R.

AU - Hwang-Verslues, W.W.

AU - Wu, C.-H.

AU - Ho, Y.-S.

N1 - Export Date: 17 October 2018 Article in Press CODEN: ETOXF Correspondence Address: Ho, Y.-S.; TMU Research Center of cancer Translational Medicine, Taipei Medical UniversityTaiwan; email: hoyuansn@tmu.edu.tw References: DeSantis, C.E., Ma, J., Goding Sauer, A., Newman, L.A., Jemal, A., Breast cancer statistics, 2017, racial disparity in mortality by state (2017) CA Cancer J Clin, 67 (6), pp. 439-448; Collins, A., Politopoulos, I., The genetics of breast cancer: risk factors for disease (2011) Appl Clin Genet, 4, pp. 11-19; Balekouzou, A., Yin, P., Pamatika, C.M., Reproductive risk factors associated with breast cancer in women in Bangui: a case-control study (2017) BMC Womens Health, 17 (1), p. 14; Hiatt, R.A., Brody, J.G., Environmental determinants of breast cancer (2018) Annu Rev Public Health; Kycler, W., Kubiak, A., Rzymski, P., Impact of selected environmental factors on attendance in the breast and cervical cancer early detection Programme in the Wielkopolska Province of Poland during 2007-2012 (2017) Ann Agric Environ Med, 24 (3), pp. 467-471; Andersen, Z.J., Stafoggia, M., Weinmayr, G., Long-term exposure to ambient air pollution and incidence of postmenopausal breast cancer in 15 European cohorts within the ESCAPE project (2017) Environ Health Perspect, 125 (10), p. 107005; Kaplanis, J., Gordon, A., Shor, T., Quantitative analysis of population-scale family trees with millions of relatives (2018) Science, 360 (6385). , 171–175; Majeed, W., Aslam, B., Javed, I., Breast cancer: major risk factors and recent developments in treatment (2014) Asian Pac J Cancer Prev, 15 (8), pp. 3353-3358; Macacu, A., Autier, P., Boniol, M., Boyle, P., Active and passive smoking and risk of breast cancer: a meta-analysis (2015) Breast Cancer Res Treat, 154 (2), pp. 213-224; Chen, C., Huang, Y.B., Liu, X.O., Active and passive smoking with breast cancer risk for Chinese females: a systematic review and meta-analysis (2014) Chin J Cancer, 33 (6), pp. 306-316; Luo, J., Margolis, K.L., Wactawski-Wende, J., Association of active and passive smoking with risk of breast cancer among postmenopausal women: a prospective cohort study (2011) BMJ, 342, p. d1016; Glantz, S.A., Johnson, K.C., The surgeon general report on smoking and health 50 years later: breast cancer and the cost of increasing caution (2014) Cancer Epidemiol Biomarkers Prev, 23 (1), pp. 37-46; Warren, G.W., Alberg, A.J., Kraft, A.S., Cummings, K.M., The 2014 surgeon General's report: "the health consequences of Smoking-50 years of Progress" a paradigm shift in cancer care (2014) Cancer, 120 (13), pp. 1914-1916; Lee, C.H., Huang, C.S., Chen, C.S., Overexpression and activation of the alpha9-nicotinic receptor during tumorigenesis in human breast epithelial cells (2010) J Natl Cancer Inst, 102 (17), pp. 1322-1335; Wei, P.L., Kuo, L.J., Huang, M.T., Nicotine enhances colon cancer cell migration by induction of fibronectin (2011) Ann Surg Oncol, 18 (6), pp. 1782-1790; Lien, Y.C., Wang, W., Kuo, L.J., Nicotine promotes cell migration through Alpha7 nicotinic acetylcholine receptor in gastric cancer cells (2011) Ann Surg Oncol, 18 (9), pp. 2671-2679; Shih, Y.L., Liu, H.C., Chen, C.S., Combination treatment with Luteolin and quercetin enhances Antiproliferative effects in nicotine-treated MDA-MB-231 cells by Down-regulating nicotinic acetylcholine receptors (2010) J Agr Food Chem, 58 (1), pp. 235-241; Lee, C.H., Chang, Y.C., Chen, C.S., Crosstalk between nicotine and estrogen-induced estrogen receptor activation induces alpha9-nicotinic acetylcholine receptor expression in human breast cancer cells (2011) Breast Cancer Res Treat, 129 (2), pp. 331-345; Chen, C.S., Lee, C.H., Hsieh, C.D., Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins (2011) Breast Cancer Res Treat, 125 (1), pp. 73-87; Tu, S.H., Ku, C.Y., Ho, C.T., Tea polyphenol (−)-epigallocatechin-3-gallate inhibits nicotine- and estrogen-induced alpha9-nicotinic acetylcholine receptor upregulation in human breast cancer cells (2011) Mol Nutr Food Res, 55 (3), pp. 455-466; Avila-Tang, E., Al-Delaimy, W.K., Ashley, D.L., Assessing secondhand smoke using biological markers (2013) Tob Control, 22 (3), pp. 164-171; Florek, E., Piekoszewski, W., Basior, A., Effect of maternal tobacco smoking or exposure to second-hand smoke on the levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in urine of mother and the first urine of newborn (2011) J Physiol Pharmacol, 62 (3), pp. 377-383; Ho, Y.S., Chen, C.H., Wang, Y.J., Tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFkappaB activation and cyclin D1 up-regulation (2005) Toxicol Appl Pharmacol, 205 (2), pp. 133-148; Wei, P.L., Chang, Y.J., Ho, Y.S., Tobacco-specific carcinogen enhances colon cancer cell migration through Alpha7-nicotinic acetylcholine receptor (vol 249, pg 978, 2009) (2009) Ann Surg, 250 (6), p. 1046; Wang, W., Chin-Sheng, H., Kuo, L.J., NNK enhances cell migration through alpha 7-nicotinic acetylcholine receptor accompanied by increased of fibronectin expression in gastric cancer (2012) Ann Surg Oncol, 19, pp. S580-S588; Song, X., Siriwardhana, N., Rathore, K., Lin, D., Wang, H.C., Grape seed proanthocyanidin suppression of breast cell carcinogenesis induced by chronic exposure to combined 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo [a]pyrene (2010) Mol Carcinog, 49 (5), pp. 450-463; Gray, J.M., Rasanayagam, S., Engel, C., Rizzo, J., State of the evidence 2017: an update on the connection between breast cancer and the environment (2017) Environmental Health, 16 (1). , 94; Ricciardiello, L., Ahnen, D.J., Lynch, P.M., Chemoprevention of hereditary colon cancers: time for new strategies (2016) Nat Rev Gastro Hepat, 13 (6), pp. 352-361; Choudhary, S., Sood, S., Donnell, R.L., Wang, H.C., Intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (2012) Carcinogenesis, 33 (4), pp. 876-885; Chen, P., Duan, X., Li, M., Systematic network assessment of the carcinogenic activities of cadmium (2016) Toxicol Appl Pharmacol, 310, pp. 150-158; Wu, K.H., Ho, C.T., Chen, Z.F., The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter (2018) J Food Drug Anal, 26 (1), pp. 221-231; Hanahan, D., Weinberg, R.A., Hallmarks of cancer: the next generation (2011) Cell, 144 (5), pp. 646-674; Mennecier, G., Torres, L.N., Cogliati, B., Chronic exposure of lung alveolar epithelial type II cells to tobacco-specific carcinogen NNK results in malignant transformation: a new in vitro lung carcinogenesis model (2014) Mol Carcinog, 53 (5), pp. 392-402; Jandial, R., (2013) Metastatic cancer : clinical and biological perspectives., , Austin, Texas, USA, Landes Bioscience; Rathore, K., Wang, H.C.R., Mesenchymal and stem-like cell properties targeted in suppression of chronically-induced breast cell carcinogenesis (2013) Cancer Lett, 333 (1), pp. 113-123; Mi, K., Xing, Z., CD44(+)/CD24(−) breast cancer cells exhibit phenotypic reversion in three-dimensional self-assembling peptide RADA16 nanofiber scaffold (2015) Int J Nanomed, 10, pp. 3043-3053; Sheridan, C., Kishimoto, H., Fuchs, R.K., CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis (2006) Breast Cancer Res, 8 (5), p. 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PY - 2018

Y1 - 2018

N2 - Breast cancer (BC) is the most common cancer affecting women worldwide and has been associated with active tobacco smoking. Low levels of nicotine (Nic) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been detected in cases of second-hand smoke (SHS). However, the correlation between SHS and BC risk remains controversial. In this study, we investigated whether the physiological SHS achievable dose of Nic and tobacco specific nitrosamine, NNK act together to induce breast carcinogenesis using an in vitro breast cell carcinogenesis model. Immortalized non-tumorigenic breast epithelial cell line, HBL-100 used for a time-course assay, was exposed to very low levels of either Nic or NNK, or both. The time-course assay consisted of 23 cycles of nitrosamines treatment. In each cycle, HBL-100 cells were exposed to 1pM of Nic and/or 100 femtM of NNK for 48 hours. Cells were passaged every 3 days and harvested after 10, 15, and 23 cycles. Our results demonstrated that the tumorigenicity of HBL-100, defined by soft agar colony forming, proliferation, migration and invasion abilities, was enhanced by co-exposure to physiologically SHS achievable doses of Nic and NNK. In addition, α9-nAChR signaling activation, which plays an important role in cellular proliferation and cell survival, was also observed. Importantly, an increase in stemness properties including the prevalence of CD44+/CD24− cells, increase Nanog expression and mammosphere-forming ability were also observed. Our results indicate that chronic and long term exposure to environmental tobacco smoke, may induce breast cell carcinogenesis even at extremely low doses. © 2018 Wiley Periodicals, Inc.

AB - Breast cancer (BC) is the most common cancer affecting women worldwide and has been associated with active tobacco smoking. Low levels of nicotine (Nic) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been detected in cases of second-hand smoke (SHS). However, the correlation between SHS and BC risk remains controversial. In this study, we investigated whether the physiological SHS achievable dose of Nic and tobacco specific nitrosamine, NNK act together to induce breast carcinogenesis using an in vitro breast cell carcinogenesis model. Immortalized non-tumorigenic breast epithelial cell line, HBL-100 used for a time-course assay, was exposed to very low levels of either Nic or NNK, or both. The time-course assay consisted of 23 cycles of nitrosamines treatment. In each cycle, HBL-100 cells were exposed to 1pM of Nic and/or 100 femtM of NNK for 48 hours. Cells were passaged every 3 days and harvested after 10, 15, and 23 cycles. Our results demonstrated that the tumorigenicity of HBL-100, defined by soft agar colony forming, proliferation, migration and invasion abilities, was enhanced by co-exposure to physiologically SHS achievable doses of Nic and NNK. In addition, α9-nAChR signaling activation, which plays an important role in cellular proliferation and cell survival, was also observed. Importantly, an increase in stemness properties including the prevalence of CD44+/CD24− cells, increase Nanog expression and mammosphere-forming ability were also observed. Our results indicate that chronic and long term exposure to environmental tobacco smoke, may induce breast cell carcinogenesis even at extremely low doses. © 2018 Wiley Periodicals, Inc.

KW - breast cancer

KW - carcinogenesis

KW - nicotine

KW - NNK

KW - second-hand smoke

KW - Cell culture

KW - Cell proliferation

KW - Cells

KW - Chemical activation

KW - Diseases

KW - Ketones

KW - Nicotine

KW - Pathology

KW - Physiological models

KW - Physiology

KW - Smoke

KW - Tissue culture

KW - Tobacco

KW - Breast Cancer

KW - Carcinogenesis models

KW - Cellular proliferations

KW - Environmental tobacco smokes

KW - Nicotinic acetylcholine receptors

KW - Second hand smokes

KW - Tobacco specific nitrosamines

KW - Cell signaling

U2 - 10.1002/tox.22659

DO - 10.1002/tox.22659

M3 - Article

JO - Environmental Toxicology

JF - Environmental Toxicology

SN - 1520-4081

ER -