Breast cancer and environmental contamination: A real connection?

Figures & data

Table 1. Sources of exposure of bisphenol A, phthalates, and parabens

Chemical compound	Source of exposure
Bisphenol A	Dentistry composites, paints, plastics, toys, food and beverage cans, polycarbonate beverage bottles, and drinking water
Phthalates	Household items, detergents, medical devices, pharmaceuticals, insecticides, toys, personal care products, food processing or packaging, and drinking water
Parabens	Personal care products, foods, beverages, and pharmaceuticals

Table 2. Bisphenol A and breast cancer research findings

Chemical compound	Experimental material	Exposure	Research finding	Authors
BPA	Nonmalignant contralateral breast tissue of patients with primary breast cancer lesion	In vitro	BPA exposure induced gene expression patterns associated with apoptosis evasion, microenvironmental stress, and deregulation of the cell cycle. These alterations were associated with large breast tumors, suggesting an important role of BFA in the aggressiveness of the tumor	Dairkee et al. (2008)
	MDEC cells (progenitor human breast epithelial cells differentiated into breast epithelial cells), and 48 breast cancer cells	In vitro	Heritable effects of BPA on nuclear localization of ERα and differential gene expression of potential biomarkers	Weng et al. (2010)
	HRBEC cells (human nonmalignant breast epithelial cells from high-risk women)	In vitro	Low concentrations of BFA can have undesirable health consequences	Goodson et al. (2011)
	HRBEC cells (human nonepithelial cells from high-risk women), and T47D breast cancer cells	In vitro	BPA induced abnormal expression of several proteins involved in cell survival, proliferation, and apoptosis	Dairkee et al. (2013)
	SkBr3 and MDA-MB-231 human breast cancer cells	In vitro	BPA promoted in vitro migration and mesenchymal transition of breast cancer cells	Zhan et al. (2015)
	Sprague Dawley rats	Gestation days 10–21 (female offspring received 7,12-dimethylbenz(a)anthracene at postnatal day 50 or 100)	Prenatal exposure to BPA increased mammary cancer susceptibility and alterations in the expression of proteins implicated in cell proliferation	Betancourt et al. (2010)
	Sprague Dawley rats, and MCF-7 human breast cancer cells	90-day-old rats	BPA induced HOTAIR expression in MCF-7 cells and in mammary glands	Bhan et al. (2014)
	Sprague Dawley rats	Pregnant dams, newborn pups until adulthood	Toxicological effects were observed at the highest BPA doses. Sample contamination affected the interpretation of the effect of lower concentrations of BPA	Churwell et al. (2014)
	Sprague Dawley rats	Gestation day 6 to postnatal day 90	Only high doses of BPA were able to depress gestational and postnatal body weight gain and affect ovary and serum hormones	Delclos et al. (2014)
	Albino rats	Female adults for 8 weeks	BPA induced structural and proliferation alterations of mammary glands	Ibrahim et al. (2016)
	Wistar rats	Perinatal exposure	BPA exposure increased mammary growth in rodents, suggesting an increased risk for developing breast cancer in women	Mandrup et al. (2016)
	CD1 mice and MCF-7 breast cancer cells	Gestational days 9–26	In utero exposure to BPA induced modifications in the epigenome of the mammary gland. BPA also induced epimutations in MCF-7 cells	Doherty et al. (2010)
	FVB/N mice, and MCF-7 human breast cancer cells	Fetal mice (offspring were treated with 7,12-dimethylbenz(a)anthracene and MCF-7 cells were subcutaneously injected)	BPA exposure augmented the risk of developing mammary cancer in mice	Weber and Keri (2011)
	C57BL/6 mice and the B6 (CAST7) or C7 strains	Two weeks prior to mating and during pregnancy until embryonic days 9.5 and 12.5	Fetal exposure to BPA induced epigenetic changes in the embryo and placenta	Susiarjo et al. (2013)
	BALB/c mice	Postnatal day 3	BPA induced an increase in tumor weight due to alterations in the immune system	Palacios-Arreola et al. (2017)

BPA: Bisphenol A.

Table 3. Phthalates and breast cancer research findings

Chemical compound		Experimental material	Exposure	Research finding	Authors
Phthalates	MCF7 human breast cancer cells and MCF10A human normal cells		In vitro	BBP induced the expression of human ERα, probably through changes in the methylation pattern of the promoter region	Kang and Lee (2005)
	MCF-7 human breast cancer cells		In vitro	MEHP activated human PPARα and PPARγ. Its toxicological consequences in the breast are complex	Venkata et al. (2006)
	MCF-7, T-47D, ZR-75-1, MDAMB-231, MDA-MB-435, and SK-BR-3 breast cancer cells		In vitro	BBP and dibutyl phthalate induced proliferation, migration, invasion, and tumor formation. Stimulation of the AhR downstream-signaling pathway, an oncogenic mechanism independent from their estrogenic activities	Hsieh, Tsai, Hsu, Kuo, Lee, et al. (2012)
	R2d human breast epithelial cancer stem cells, MCF-7 human breast cancer cells, and HUVECs human umbilical vein endothelial cells		In vitro	BBP exposure altered the expression of certain genes involved in proliferation, epithelial–mesenchymal transition, and angiogenesis signaling by more than 10-folds in R2d cells. Induced the viability, invasion and migration, and tube formation in vitro, and angiogenesis in vivo of R2d and MCF-7 cells	Hsieh, Tsai, Hsu, Kuo, Hsi, et al. (2012)
	MCF-7 and MDA-MB-231 human breast cancer cells		In vitro	In vitro DEHP exposure induced proliferation of MCF-7 and MDA-MB-231 cells. DEHP also suppressed tamoxifen induced apoptosis in both cell types	Das et al. (2014)
	MDA-MB-231 human breast cancer cells, HUVECs human umbilical vein endothelial cells, and 4T1 mouse mammary tumor cell line		In vitro	BBP was able to remodel the breast cancer tumor microenvironment, influencing the efficacy of chemotherapy	Hsu et al. (2015)
	MCF-7 and MDA-MB-231 human breast cancer cells, and Nu/Nu immunodeficient mice		In vitro	Phthalates stimulated breast tumor-initiating cells in human breast cancer cell cultures and xenograft tumors	Wang et al. (2016)
	Sprague Dawley rats		Gestational day 14 to postnatal day 3	DEHP, BBP, and DiNP affected sexual differentiation	Gray et al. (2000)
	Wistar rats		Gestational day 6 to lactation day 21	DEHP exposure only increased the number of ovarian atretic tertiary follicles; no other effects were observed	Grande et al. (2006)
	Wistar–Imamichi rats		Postnatal days 22–41 and to 84	Inhalation of DEHP may alter the onset of puberty and postpubertal reproductive functions	Ma et al. (2006)
	C57/Bl6 mice		Gestational days 17–19	MEHP exposure induced early ovarian senescence and mammary hyperplasia	Moyer and Hixon (2012)
	Clinical studies	Puerto Rican girls with premature breast development (case-control study)		Probable association between plasticizers with estrogenic and antiandrogenic activities and premature breast development in girls	Colón et al. (2000)
		Girls in early puberty (case-control study)		MMP in girls may cause early puberty in Taiwanese girls	Chou et al. (2009)
		Mexican women with breast cancer (case-control study)		Exposure to diethyl phthalate may be associated with higher risk of breast cancer	López-Carrillo (2010)
		Women from the AN Medical Center (case-control study)		Exposure to the parent compound of the phthalate metabolite MEHP could be associated with breast cancer	Holmes et al. (2014)
		Girls with central precocious puberty and prepubertal (multicenter cross-sectional study)		Phthalates exposure was not associated with premature puberty in girls	Lomenick et al. (2010)
		Mexican-American newborns (longitudinal birth cohort study)	In utero	Prenatal phthalate exposure induced differential DNA methylation patterns in newborns	Solomon et al. (2017)

AhR: Aryl hydrocarbon receptor; BBP: butyl benzyl phthalate; DEHP: di-(2-ethylhexyl) phthalate; DiNP: di-isononylphthalate; MEHP: mono-(2-ethylhexyl) phthalate; MMP: monomethyl phtalate; ER: estrogen receptor; PPAR: peroxisome proliferator-activated receptor.

Table 4. Parabens and breast cancer research findings

Chemical compound	Experimental material		Exposure	Research finding	Authors
Parabens	HRBEC cells (human nonmalignant breast epithelial cells from high-risk women)		In vitro	Low concentrations of methylparaben can have undesirable health consequences	Goodson et al. (2011)
	MCF-7 human breast cancer cells		In vitro	Even though parabens possess estrogenic properties, global gene expression patterns are not equal to 17β-estradiol	Pugazhendhi et al., 2007
	MCF-7 human breast cancer cells		In vitro	Five parabens were present in human breast tissue at concentrations capable to stimulate MCF-7 cells proliferation	Charles and Darbre (2013)
	MCF-7, T-47-D, and ZR-75-1 human breast cancer cells		In vitro	In vitro long-term exposure of parabens can influence proliferation, migration, and invasive properties of human breast cancer cells	Khanna et al. (2014)
	MCF-7 human breast cancer cells and MCF-10A nonmalignant cells		In vitro	Differences in the expression of cell cycle and apoptotic genes were induced with parabens and 17β-estradiol in MCF-7 cells, but not in MCF-10A cells	Wróbel and Greoraszczzuk (2014)
	BT-474 human breast cancer cells		In vitro	HER ligands enhanced the potency of butylparaben to induce oncogene expression and breast cancer cell proliferation, suggesting that parabens might be toxicologically active at low levels	Pan et al. (2016)
	Sprague Dawley rats		Perinatal, prepubertal, and pubertal periods, and from birth to lactation	Low-dose exposure to methyl paraben induced alterations in mammary histology and transcriptome	Gopalakrishan et al. (2017)
	Clinical studies	Women from general population		Elevated levels of native parabens were associated with the use of skin lotions, suggesting that their regular use preserve elevated concentrations regardless of parabens short half-lives	Sandager et al. (2011)
		Breast cancer tissue of women from England		Different parabens were quantifiable, with the highest levels for n-propylparaben and methylparaben. The source of the paraben cannot be identified	Barr et al. (2012)

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