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The contribution of heavy metals in cigarette smoke condensate to malignant transformation of breast epithelial cells and in vivo initiation of neoplasia through induction of a PI3K-AKT-NFκB cascade

Mohapatra, Purusottam LU ; Preet, Ranjan ; Das, Dipon ; Satapathy, Shakti Ranjan LU ; Siddharth, Sumit ; Choudhuri, Tathagata ; Wyatt, Michael D and Kundu, Chanakya Nath (2014) In Toxicology and Applied Pharmacology 274(1). p.79-168
Abstract

Cigarette smoking is a crucial factor in the development and progression of multiple cancers including breast. Here, we report that repeated exposure to a fixed, low dose of cigarette smoke condensate (CSC) prepared from Indian cigarettes is capable of transforming normal breast epithelial cells, MCF-10A, and delineate the biochemical basis for cellular transformation. CSC transformed cells (MCF-10A-Tr) were capable of anchorage-independent growth, and their anchorage dependent growth and colony forming ability were higher compared to the non-transformed MCF-10A cells. Increased expression of biomarkers representative of oncogenic transformation (NRP-1, Nectin-4), and anti-apoptotic markers (PI3K, AKT, NFκB) were also noted in the... (More)

Cigarette smoking is a crucial factor in the development and progression of multiple cancers including breast. Here, we report that repeated exposure to a fixed, low dose of cigarette smoke condensate (CSC) prepared from Indian cigarettes is capable of transforming normal breast epithelial cells, MCF-10A, and delineate the biochemical basis for cellular transformation. CSC transformed cells (MCF-10A-Tr) were capable of anchorage-independent growth, and their anchorage dependent growth and colony forming ability were higher compared to the non-transformed MCF-10A cells. Increased expression of biomarkers representative of oncogenic transformation (NRP-1, Nectin-4), and anti-apoptotic markers (PI3K, AKT, NFκB) were also noted in the MCF-10A-Tr cells. Short tandem repeat (STR) profiling of MCF-10A and MCF-10A-Tr cells revealed that transformed cells acquired allelic variation during transformation, and had become genetically distinct. MCF-10A-Tr cells formed solid tumors when implanted into the mammary fat pads of Balb/c mice. Data revealed that CSC contained approximately 1.011μg Cd per cigarette equivalent, and Cd (0.0003μg Cd/1×10(7) cells) was also detected in the lysates from MCF-10A cells treated with 25μg/mL CSC. In similar manner to CSC, CdCl2 treatment in MCF-10A cells caused anchorage independent colony growth, higher expression of oncogenic proteins and increased PI3K-AKT-NFκB protein expression. An increase in the expression of PI3K-AKT-NFκB was also noted in the mice xenografts. Interestingly, it was noted that CSC and CdCl2 treatment in MCF-10A cells increased ROS. Collectively, results suggest that heavy metals present in cigarettes of Indian origin may substantially contribute to tumorigenesis by inducing intercellular ROS accumulation and increased expression of PI3K, AKT and NFκB proteins.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Breast/drug effects, Breast Neoplasms/metabolism, Cell Line, Transformed, Cell Transformation, Neoplastic/chemically induced, Dose-Response Relationship, Drug, Epithelial Cells/drug effects, Female, Humans, Metals, Heavy/toxicity, Mice, Mice, Inbred BALB C, NF-kappa B/biosynthesis, Phosphatidylinositol 3-Kinase/biosynthesis, Proto-Oncogene Proteins c-akt/biosynthesis, Smoke/adverse effects, Smoking/adverse effects, Xenograft Model Antitumor Assays/methods
in
Toxicology and Applied Pharmacology
volume
274
issue
1
pages
79 - 168
publisher
Academic Press
external identifiers
  • pmid:24099783
  • scopus:84890428113
ISSN
1096-0333
DOI
10.1016/j.taap.2013.09.028
language
English
LU publication?
no
additional info
© 2013.
id
d96a3be3-23f2-45c4-bc03-da690df6f6d9
date added to LUP
2025-01-30 10:31:57
date last changed
2025-06-20 14:36:37
@article{d96a3be3-23f2-45c4-bc03-da690df6f6d9,
  abstract     = {{<p>Cigarette smoking is a crucial factor in the development and progression of multiple cancers including breast. Here, we report that repeated exposure to a fixed, low dose of cigarette smoke condensate (CSC) prepared from Indian cigarettes is capable of transforming normal breast epithelial cells, MCF-10A, and delineate the biochemical basis for cellular transformation. CSC transformed cells (MCF-10A-Tr) were capable of anchorage-independent growth, and their anchorage dependent growth and colony forming ability were higher compared to the non-transformed MCF-10A cells. Increased expression of biomarkers representative of oncogenic transformation (NRP-1, Nectin-4), and anti-apoptotic markers (PI3K, AKT, NFκB) were also noted in the MCF-10A-Tr cells. Short tandem repeat (STR) profiling of MCF-10A and MCF-10A-Tr cells revealed that transformed cells acquired allelic variation during transformation, and had become genetically distinct. MCF-10A-Tr cells formed solid tumors when implanted into the mammary fat pads of Balb/c mice. Data revealed that CSC contained approximately 1.011μg Cd per cigarette equivalent, and Cd (0.0003μg Cd/1×10(7) cells) was also detected in the lysates from MCF-10A cells treated with 25μg/mL CSC. In similar manner to CSC, CdCl2 treatment in MCF-10A cells caused anchorage independent colony growth, higher expression of oncogenic proteins and increased PI3K-AKT-NFκB protein expression. An increase in the expression of PI3K-AKT-NFκB was also noted in the mice xenografts. Interestingly, it was noted that CSC and CdCl2 treatment in MCF-10A cells increased ROS. Collectively, results suggest that heavy metals present in cigarettes of Indian origin may substantially contribute to tumorigenesis by inducing intercellular ROS accumulation and increased expression of PI3K, AKT and NFκB proteins.</p>}},
  author       = {{Mohapatra, Purusottam and Preet, Ranjan and Das, Dipon and Satapathy, Shakti Ranjan and Siddharth, Sumit and Choudhuri, Tathagata and Wyatt, Michael D and Kundu, Chanakya Nath}},
  issn         = {{1096-0333}},
  keywords     = {{Animals; Breast/drug effects; Breast Neoplasms/metabolism; Cell Line, Transformed; Cell Transformation, Neoplastic/chemically induced; Dose-Response Relationship, Drug; Epithelial Cells/drug effects; Female; Humans; Metals, Heavy/toxicity; Mice; Mice, Inbred BALB C; NF-kappa B/biosynthesis; Phosphatidylinositol 3-Kinase/biosynthesis; Proto-Oncogene Proteins c-akt/biosynthesis; Smoke/adverse effects; Smoking/adverse effects; Xenograft Model Antitumor Assays/methods}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{79--168}},
  publisher    = {{Academic Press}},
  series       = {{Toxicology and Applied Pharmacology}},
  title        = {{The contribution of heavy metals in cigarette smoke condensate to malignant transformation of breast epithelial cells and in vivo initiation of neoplasia through induction of a PI3K-AKT-NFκB cascade}},
  url          = {{http://dx.doi.org/10.1016/j.taap.2013.09.028}},
  doi          = {{10.1016/j.taap.2013.09.028}},
  volume       = {{274}},
  year         = {{2014}},
}