Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells

Francescopaolo Di Cello, V. Lynn Flowers, Huili Li, Briana Vecchio-Pagán, Brent Gordon, Kirsten Harbom, James Shin, Robert Beaty, Wei Wang, Cory Brayton, Stephen B Baylin, Cynthia Zahnow

Research output: Contribution to journalArticle

Abstract

Background: Recent epidemiological studies demonstrate that both active and involuntary exposure to tobacco smoke increase the risk of breast cancer. Little is known, however, about the molecular mechanisms by which continuous, long term exposure to tobacco smoke contributes to breast carcinogenesis because most previous studies have focused on short term treatment models. In this work we have set out to investigate the progressive transforming effects of tobacco smoke on non-tumorigenic mammary epithelial cells and breast cancer cells using in vitro and in vivo models of chronic cigarette smoke exposure.Results: We show that both non-tumorigenic (MCF 10A, MCF-12A) and tumorigenic (MCF7) breast epithelial cells exposed to cigarette smoke acquire mesenchymal properties such as fibroblastoid morphology, increased anchorage-independent growth, and increased motility and invasiveness. Moreover, transplantation experiments in mice demonstrate that treatment with cigarette smoke extract renders MCF 10A cells more capable to survive and colonize the mammary ducts and MCF7 cells more prone to metastasize from a subcutaneous injection site, independent of cigarette smoke effects on the host and stromal environment. The extent of transformation and the resulting phenotype thus appear to be associated with the differentiation state of the cells at the time of exposure. Analysis by flow cytometry showed that treatment with CSE leads to the emergence of a CD44hi/CD24low population in MCF 10A cells and of CD44+ and CD49f + MCF7 cells, indicating that cigarette smoke causes the emergence of cell populations bearing markers of self-renewing stem-like cells. The phenotypical alterations induced by cigarette smoke are accompanied by numerous changes in gene expression that are associated with epithelial to mesenchymal transition and tumorigenesis.Conclusions: Our results indicate that exposure to cigarette smoke leads to a more aggressive and transformed phenotype in human mammary epithelial cells and that the differentiation state of the cell at the time of exposure may be an important determinant in the phenotype of the final transformed state.

Original languageEnglish (US)
Article number90
JournalMolecular Cancer
Volume12
Issue number1
DOIs
StatePublished - Aug 6 2013

Fingerprint

Epithelial-Mesenchymal Transition
Smoke
Tobacco Products
Breast Neoplasms
Breast
Tobacco
Epithelial Cells
MCF-7 Cells
Phenotype
Cell Differentiation
Carcinogenesis
Subcutaneous Injections
Population
Epidemiologic Studies
Flow Cytometry
Stem Cells
Therapeutics
Transplantation
Gene Expression

Keywords

  • Breast cancer
  • Cell motility and invasion
  • Epithelial to mesenchymal transition
  • Intraductal injection
  • Metastasis
  • Tobacco

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Oncology

Cite this

Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells. / Di Cello, Francescopaolo; Flowers, V. Lynn; Li, Huili; Vecchio-Pagán, Briana; Gordon, Brent; Harbom, Kirsten; Shin, James; Beaty, Robert; Wang, Wei; Brayton, Cory; Baylin, Stephen B; Zahnow, Cynthia.

In: Molecular Cancer, Vol. 12, No. 1, 90, 06.08.2013.

Research output: Contribution to journalArticle

Di Cello, Francescopaolo ; Flowers, V. Lynn ; Li, Huili ; Vecchio-Pagán, Briana ; Gordon, Brent ; Harbom, Kirsten ; Shin, James ; Beaty, Robert ; Wang, Wei ; Brayton, Cory ; Baylin, Stephen B ; Zahnow, Cynthia. / Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells. In: Molecular Cancer. 2013 ; Vol. 12, No. 1.
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abstract = "Background: Recent epidemiological studies demonstrate that both active and involuntary exposure to tobacco smoke increase the risk of breast cancer. Little is known, however, about the molecular mechanisms by which continuous, long term exposure to tobacco smoke contributes to breast carcinogenesis because most previous studies have focused on short term treatment models. In this work we have set out to investigate the progressive transforming effects of tobacco smoke on non-tumorigenic mammary epithelial cells and breast cancer cells using in vitro and in vivo models of chronic cigarette smoke exposure.Results: We show that both non-tumorigenic (MCF 10A, MCF-12A) and tumorigenic (MCF7) breast epithelial cells exposed to cigarette smoke acquire mesenchymal properties such as fibroblastoid morphology, increased anchorage-independent growth, and increased motility and invasiveness. Moreover, transplantation experiments in mice demonstrate that treatment with cigarette smoke extract renders MCF 10A cells more capable to survive and colonize the mammary ducts and MCF7 cells more prone to metastasize from a subcutaneous injection site, independent of cigarette smoke effects on the host and stromal environment. The extent of transformation and the resulting phenotype thus appear to be associated with the differentiation state of the cells at the time of exposure. Analysis by flow cytometry showed that treatment with CSE leads to the emergence of a CD44hi/CD24low population in MCF 10A cells and of CD44+ and CD49f + MCF7 cells, indicating that cigarette smoke causes the emergence of cell populations bearing markers of self-renewing stem-like cells. The phenotypical alterations induced by cigarette smoke are accompanied by numerous changes in gene expression that are associated with epithelial to mesenchymal transition and tumorigenesis.Conclusions: Our results indicate that exposure to cigarette smoke leads to a more aggressive and transformed phenotype in human mammary epithelial cells and that the differentiation state of the cell at the time of exposure may be an important determinant in the phenotype of the final transformed state.",
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AU - Di Cello, Francescopaolo

AU - Flowers, V. Lynn

AU - Li, Huili

AU - Vecchio-Pagán, Briana

AU - Gordon, Brent

AU - Harbom, Kirsten

AU - Shin, James

AU - Beaty, Robert

AU - Wang, Wei

AU - Brayton, Cory

AU - Baylin, Stephen B

AU - Zahnow, Cynthia

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AB - Background: Recent epidemiological studies demonstrate that both active and involuntary exposure to tobacco smoke increase the risk of breast cancer. Little is known, however, about the molecular mechanisms by which continuous, long term exposure to tobacco smoke contributes to breast carcinogenesis because most previous studies have focused on short term treatment models. In this work we have set out to investigate the progressive transforming effects of tobacco smoke on non-tumorigenic mammary epithelial cells and breast cancer cells using in vitro and in vivo models of chronic cigarette smoke exposure.Results: We show that both non-tumorigenic (MCF 10A, MCF-12A) and tumorigenic (MCF7) breast epithelial cells exposed to cigarette smoke acquire mesenchymal properties such as fibroblastoid morphology, increased anchorage-independent growth, and increased motility and invasiveness. Moreover, transplantation experiments in mice demonstrate that treatment with cigarette smoke extract renders MCF 10A cells more capable to survive and colonize the mammary ducts and MCF7 cells more prone to metastasize from a subcutaneous injection site, independent of cigarette smoke effects on the host and stromal environment. The extent of transformation and the resulting phenotype thus appear to be associated with the differentiation state of the cells at the time of exposure. Analysis by flow cytometry showed that treatment with CSE leads to the emergence of a CD44hi/CD24low population in MCF 10A cells and of CD44+ and CD49f + MCF7 cells, indicating that cigarette smoke causes the emergence of cell populations bearing markers of self-renewing stem-like cells. The phenotypical alterations induced by cigarette smoke are accompanied by numerous changes in gene expression that are associated with epithelial to mesenchymal transition and tumorigenesis.Conclusions: Our results indicate that exposure to cigarette smoke leads to a more aggressive and transformed phenotype in human mammary epithelial cells and that the differentiation state of the cell at the time of exposure may be an important determinant in the phenotype of the final transformed state.

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