Table 1.

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

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	Unestablished
	[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	Unestablished
	[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)	Unestablished 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)	Unestablished
	[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