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Table 1 Breast cancer findings for environmental chemical disruptors in experimental studies that investigated cancer progression and targeted signal pathways

From: Environmental chemicals, breast cancer progression and drug resistance

Potential environmental chemical disruptors Studies (ref) Type of study (in vitro/in vivo) Effects that chemicals may have Targeted signal pathways
Persistent EDCs
 Dioxin [9] In vivo ↓ tumor growth in immature 120-150 g female Sprague-Dawley rat (no more precision) Unestablished
[10] In vitro ↓ invasion, motility and colony formation (MDA-MB-231, MCF7, ZR75, SKBR3)
↑ differenciation in a putative mammary cancer stem cell line
AhR dependant pathway regardless to ER status
[11] In vivo/ In vitro ↓ proliferation (MCF7)
↓ tumor growth in male B6D2F mice (
Antagonistic effect on ER signaling
[12] In vitro ↓ proliferation (MCF7, TD47, ZR75) Antagonistic effect on ER signaling
[13] In vitro ↓ migration (MCF7) Downregulation of CXCR4 and CXCL12
[14] In vivo/ In vitro ↓ metastasis formation in BALB/C mice (from NCI Charles Rivers, Frederick, MD, USA)
No effect on tumor growth nor cell proliferation
[15] In vitro ↑ cell migration NFATc1/ATX-signaling pathway
[16] In vitro EMT, ↑ migration AhR pathway
[17] In vitro ↑ invasion
Resistance to apoptosis
Mitochondrial dysfonction (↑ cytosolic [Ca(2+)](c) and RyR1-specific Ca(2+) release, ↑ calcineurin (CnA) levels and activation of its factors.
Mitochondrial transmembrane potential disruption in a time-dependent way
Mitochondrial transcription and translation inhibition
Activation of CnA-sensitive NF-kappaB/Rel (IkappaBbeta-dependent) factors.
[18] In vivo/ In vitro ↓ colony formation (BP1, Hs578T, SUM149)
↑ migration
↓ metastasis (2-days zebrafish larvae AB x Fli-GFP)
AhR signaling pathway
 Polychlorinated biphenyls [19] In vivo/ In vitro ↑ migration (MCF7, MDA-MB-231
↑ growth tumor and metastasis in NOD SCID immune- deficient mice (no more precision)
ROCK signaling pathway
[20] In vitro ↑ transendothelial migration (MDA-MB-231) Overexpression of VEGF through PI3K pathway signaling
[21]   ↑ transendothelial migration, ↑MMP3 (human endothelial cells) Activation EGFR and JAK3 in a coordinated and cross-regulated way
AK3 and EGFR stimulate in concert PCB-induced activation of JNK and ERK1/2 followed by increased DNA binding of AP-1 and PEA3 and transcriptional up-regulation of MMP-3 expression.
DDT/DDE and organochlorine pesticides
 DDT/DDE [22] In vivo ↑ ER + tumor growth in 150 g Wistar Furth ovariectomized rat (from Harlan Sprague Dawley, Madison, WI)
↑ proliferation MT2 and MTW9/PL estrogen responsive mammary adenocarcinoma
ER signaling pathway
Estrogen-androgen balance disruption
[23] In vitro ↑ proliferation in CAMA-1 human ER+ breast cancer cells Opposing androgen signalling pathway that inhibits growth in hormone-responsive
 Hexachlorobenzene [24] In vitro ↑ proliferation (MCF7) IGF-I) signaling pathway
[25] In vitro ↑ migration (MDA-MB-231) c-Src/HER1/STAT5b and HER1/ERK1/2 signaling pathways
[26] In vivo/ In vitro ↑ invasion and MMP2/9 (MDA-MB-231)
↑ metastasis in mice (regardless ER status) in nude female Swiss BALB/C mice (La Plata Laboratory Animal Facility, Buenos Aires, Argentina)
AhR, c-Src, HER1, STAT5b, and ERK1/2 signaling pathways
[27] In vitro ↑ migration and invasion Modulation of the crosstalk between AhR and TGFβ signaling
Consumer product chemicals
 Bisphenol A [28] In vitro ↑ expression MMP2/ MMP9 in TNBC –triple negative breast cancer (MDA-MB-231 and BT-549) Activation ERRγ through ERK1/2 and Akt pathway
[29] In vitro ↑ proliferation and invasion in TNBC –triple negative breast cancer (MDA-MB-231 and BT-549) Unestablished
[30, 31] In vitro ↑ proliferation (MCF7) Upregulation of cell cycle genes
Downregulation of antiproliferative genes
[32] In vitro Alteration of the expression of cell cycle related genes Activation of Estrogen Receptor dependent signaling pathway
[33] In vitro ↑ proliferation
Induction of a profile of tumor aggressiveness in high-risk cells from breast cancer patients
[34, 35] In vitro ↑ migration and invasion (MDA-MB-231) Activation GPER dependant pathway
Activation of FAK, Src, ERK2-dependant pathway
 Phtalates [36] In vitro Phenotypical and gene expression changes associated with EMT (R2d cells, stem cell derived human breast epithelial cell line) Activation of EGFR-PKA signaling cascade that increase AP2a transcriptor factor which upregulate histone deacetylase 3
[37] In vitro/In vivo ↑ proliferation, migration and colony formation (MDA-MB-231)
↑ tumor formation in Female nude mice BALB/cAnN.Cg-Foxn1nu/CrlNarl, 4–6 wk. old (from the National Laboratory Animal Center Taipei, Taiwan)
AhR/HDAC6/c-Myc signaling pathway
[38] In vitro ↑ proliferation (MCF7) Activation of PPARα and γ
[39] In vitro ↑ proliferation (MCF7) P13K/AKT signaling pathway
[40] In vitro ↓ tamoxifen-induced apoptosis in ER+ cells (MCF7) but not ER- cells (MDA-MB-231 Increased Bcl-2 to Bax ratio through an Estrogen Receptor dependent signaling pathway
 Benzophénone-1/Nonylphenol [41] In vitro ↑ proliferation and migration (MCF7) Upregulation of cyclin D1 and cathepsin D and downregulation in p21 regulated by an ERα-dependent pathway
 Per and polyfluoroalkyl acids
  PFOA [42] In vitro ↑ proliferation, migration and invasion (MCF10) Upregulation of cyclin D1 and CDK4/6 and downregulation and in p27 through PPARα-dependant pathway
  PFOS [43] In vitro ↑ proliferation, migration and invasion (MCF10) Upregulation of CDK4 and down regulation and downregulation in p27, p21 and p53
Food preparation
 Benzo(A)pyrene [35] In vitro ↑ migration (MDA-MB-231, MCF7)
↑ αvβ3 integrin-cell surface levels and an increase of metalloproteinase (MMP)-2 and MMP-9
Lipoxygenase- and Src-dependent pathway
Activation of FAK, Src and extracellular signal-regulated kinase 2
[44] In vitro ↑ invasion (MDA-MB-231) Upregulation of COX II and PGE2 through an AhR signaling pathway
[45] In vivo/In vitro ↑ migration and invasion, ↑MMP9 (MCF7)
↑ growth tumor and liver and lung metastasis in an accumulative mouse model mimicking the cumulative effects of chronic BaP exposure in female BALB/C mice (from the Shanghai Laboratory Animal, China)
Upregulation of ROS-induced ERK signaling pathway
 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [46] In vitro ↑ migration and invasion, ↑ MMP9 (MCF7, TD47) Upregulation of Cathepsin D and cyclooxygenase 2 through ER signaling
[47] In vivo/In vitro Carcinogenesis effects, ↑ proliferation, migration, invasion, ↑ colony formation and stem-like cell populations (MCF10)
↑tumorigenicity, ↑ lung metastasis in athymic NCS-nu/nu mice ((no more precision)
Ras-ERK-Nox-ROS signaling pathway
Other polycyclic aromatic carbons
 Cigarette smoke [48] In vivo ↑ total pulmonary metastatic burden in smoke-exposed animals (female sexually mature BALB/cAnN mice) (from Charles River Laboratories, Wilmington, MA, USA) Unestablished
[49] In vitro/ In vivo Phenotypical and gene expression changes associated with EMT (MCF7)
Emergence of stem-like cells population, colony formation
↓ tumor size
↑ lung metastasis and liver cancer cells in female immuno deficient NSG mice (from The Jackson Laboratory, Bar Harbor, ME, USA)
Activation of nAChRs, Src and calcium-dependent signaling pathway
[50] In vitro ↑ proliferation and invasion
↑ migration in a dose-dependent manner
Phenotypical and gene expression changes associated with EMT (MCF7 and MDA-MB-468)
[51] In vitro ↑ proliferation
↑ of stem-like cells population
Resistance to Doxorubicin
 7,12-dimethylbenz(a)anthracene [52] In vitro ↑ proliferation and invasion (mice)
↑ colony formation
EMT (↓ E cadherin)
NFκB pathway
Alcohol [53] (review) In vitro/ in vivo ↑Angiogenesis, migration, invasion, EMT, MMP
↑ Cancer stem cells
↑ Metastasis formation in MMTV neu transgenic mice (no more precision)
Cross-talk between oxidative stress and EGFR/ErbB2 signaling
Toxic metals [54] In vitro Cadmium ↑ migration and invasion (MCF7, MDA-MB-231) TGIF/MMP2 signaling axis
[55] In vivo/ In vitro Tungsten ↓ primary tumor growth but ↑metastasis in female BALB/C mice
No change observed in invasiveness of cells in vitro (66Cl4 model of breast cancer metastasis to bone) (from Charles Rivers Laboratories, Montréal, Canada)
Targeting microenvironment: activation CAFs at the metastatic site (↑ MMP9) and ↑ of myeloid-derived suppressor cells