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Parabens Exposure and Breast Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/ijerph19031873

There is increasing recognition that environmental exposure to chemicals, such as endocrine-disruptive chemicals (EDCs), contributes to the development of breast cancer. Parabens are a group of EDCs commonly found in personal care products, foods, and pharmaceuticals. Systemic exposure to parabens has been confirmed by the ubiquitous detection of parabens in human blood and urine samples. Although evidence from in vivo and epidemiological studies linking parabens exposure to breast cancer is limited, the current evidence suggests that parabens may negatively interfere with some endocrine and intracrine targets relevant to breast carcinogenesis. So far, most studies have focused on a single paraben’s effects and the direct modulating effects on estrogen receptors or the androgen receptor in vitro. Recent studies have revealed that parabens can modulate local estrogen-converting enzymes, 17β-hydroxysteroid dehydrogenase 1 and 2 and increase local estrogen levels. Also, parabens can crosstalk with the human epidermal growth factor receptor 2 (HER2) pathway and work with ER signaling to increase pro-oncogenic c-Myc expression in ER+/HER2+ breast cancer cells. Future studies investigating paraben mixtures and their crosstalk with other EDCs or signaling pathways both in vitro and in vivo in the context of breast cancer development are warranted. 

paraben breast cancer endocrine-disruptive chemicals

1. Introduction

Breast cancer remains the second leading cause of cancer deaths (only second to lung cancer) in women in the US in 2021. It is estimated that more than 40,000 women will die from breast cancer in 2021 [1]. The average risk of a woman developing breast cancer at some time in her life is about 13% [1].
The risk factors for breast cancer have been identified and are grouped into non-modifiable (familial and hereditary) factors and modifiable (environmental) factors [2]. The familial risk factors include a family history of breast cancer, other breast diseases, or high breast density. Women with inherited mutations, specifically in BRCA1 and BRCA2, may have a higher breast cancer risk. The genetic risks of breast cancer only account for approximately 5–10% of breast cancers, whereas 90% of breast cancer occurrence is thought to be environment-related [2]. The most commonly known modifiable risk factors for breast cancer are obesity, sedentary lifestyle, having a first child after 30, post-menopausal hormone and oral contraceptives use, and xenoestrogen exposure [3].
A growing body of evidence from animal and human studies links exposure to environmental chemicals with increased risks of developing breast cancer. Among them are endocrine-disrupting chemicals (EDCs) [4][5][6]. EDCs are exogenous chemicals that can interfere with endogenous hormone action with key characteristics, including activating or antagonizing hormone receptors or altering receptor expression and downstream signaling events in the sensitive cells [7]. The most common examples of EDCs are dioxins, polychlorinated biphenyls, bisphenol A, and parabens found in products such as plastics, detergents, foods, toys, cosmetics, or pharmaceuticals [8]. Parabens are 4-hydroxybenzoic acid alkyl esters. Emerging evidence has now revealed the endocrine-disrupting propensity of parabens based on their adverse impact on development and reproduction from both in vitro and in vivo studies [9][10].

2. Parabens Exposure and Breast Cancer

Like many other EDCs, paraben exposure has been associated with poor reproductive health in women [11]. In a recent study, urinary parabens concentrations were associated with earlier breast development, pubic hair development, earlier menarche in girls, and earlier genital development in boys [12].
It has been postulated that exposure to some EDCs leads to exacerbated cell proliferation and tumor growth in the breasts [2][4][13]. To establish links between parabens and breast cancer, it is imperative to demonstrate the presence and localization of parabens within the breast tissue. Paraben levels in breast tissue extracted from axilla to sternum have been investigated [14][15]. MP was detected at approximately 16.6 ng per gram of the breast tissue, higher than previously documented [16]. The tissue level of PP was 16.8 ng/g, higher than MP. Other parabens, such as BP, EP, and IsoBP, were also detected, although at relatively lower levels [14]. However, no significant correlation was identified between the concentration of parabens and the location of breast tumors or the estrogen receptor status in the breast tumors. It has been shown that parabens have greater bioaccumulation within the outer areas (axilla and lateral) of the breast than the inner areas (mid and medial) [15]. The outer areas of the breast consist of more adipose tissue where the mammary glands are centrally located. Moreover, the detection and accumulation of parabens in the adipose tissue of the breast have been reported, possibly due to their moderate hydrophobicity [17]. Higher levels of parabens detected in the outer regions of the breasts might be associated with how deodorants are applied [15].
Perhaps due to the vast amount of exposure variability and weak estrogenicity of parabens (reviewed in more details below) compared to 17-β Estradiol, epidemiological evidence directly linking parabens exposure with breast cancer is still limited. In one study, the association between the circulating level of xenoestrogens and mammographic breast density, a powerful risk factor for breast cancer, was investigated in post-menopausal women. No association was found between serum levels of BP or PP and the density of the breasts [18][19]. In a recent case-control study, paraben levels in spot urine samples from 711 women with breast cancer were analyzed and compared with the 598 women without breast cancer [20]. It was found that the highest quintiles of urinary MP (414–3174 μg/g creatinine), PP (28–3116 μg/g creatinine), and total parabens (551–3766 μg/g creatinine) were associated with increased risks of breast cancer and all-cause mortality [20]. In addition, the associations were affected by body mass index (BMI). Associations for breast cancer incidence were more pronounced among women with lower BMI (BMI < 25.0 kg/m2) than among women with higher BMI (BMI ≥ 25.0 kg/m2). In contrast, associations for mortality were shown to have an opposite trend with BMI [20]. In another case-control study with a multiethnic cohort, urinary parabens and other EDCs in 1032 post-menopausal women with breast cancer with different ethnic backgrounds and 1030 individually matched controls were analyzed [21]. Breast cancer risks in this multiethnic population were weakly inversely associated with paraben exposure [21]. It should be noted that prolonged daily exposure to a paraben mixture (i.e., more than one type of parabens), bioaccumulation, and interactions with other xenoestrogens can invoke local intracrine, paracrine, or endocrine changes, contributing to breast carcinogenesis [22]. Therefore, future investigations on the association of parabens with breast cancer are needed. Table 1 summarizes the strengths and limitations of human studies on parabens exposure and breast cancer.
Table 1. Summary of Human Studies on Paraben Exposure and Breast Cancer.
Table
  Conclusions Strength Limitations
Darbre et al. 2004 [16]. Intact parabens were found in the human breast tumor tissues. MP was present at the highest level and represented 62% of the total parabens extracted from breast tumor tissues. Demonstrated that after exposure, a proportion of the parabens can remain intact in human body tissues. The levels of parabens measured in this study were comparable to the levels of parabens used in in vitro studies, indicating the levels of parabens detected in breast tissues could induce estrogenic effects in the human breast. Small sample size. Analytical blank values might contain parabens introduced from other sources.
Barr et al. 2011 [15]. Parabens were detected across the human breast from axilla to sternum. PP was found at significantly higher levels in the axilla than mid or medial regions of the breast. No correlations were found between paraben concentrations and tumor location or tumor estrogen receptor content. Measured at the earliest time point possible after cancer diagnosis and prior to any cancer therapy. Investigated the distribution of parabens across a single breast. Parabens were detected in breast tissues from human subjects who self-reported as non-underarm cosmetics users. Parabens were measured from breast tissues adjacent to breast tumor but not from tumor directly. It is also unclear the relative importance of long-term accumulation and/or acute exposure to the levels of parabens in the breast tissue.
Sprague et al. 2013 [19]. Serum concentrations of BP and PP were modestly correlated, but parabens concentrations were not associated with percentage breast density (a marker of breast cancer risk). Evaluated mammographic breast density in relation to biological measures of xenoestrogens, including parabens. Serum measurements may better reflect the biologically relevant exposure of the target organs. Only postmenopausal women were enrolled in the study. Single blood sample was collected, which may only reflect current exposure. The study population was predominately non-Hispanic white. The results may not apply to general population.
Harley, et al. 2019 [12]. Peripubertal concentrations of MP were associated with earlier breast development, pubic hair development, and menarche in girls; peripubertal concentrations of PP were associated with earlier pubic hair development in girls; peripubertal PP concentrations were associated with earlier genital development in boys. Evaluated prenatal as well as peripubertal parabens exposure. Urinary parabens only reflected recent exposure. The study population was limited to Latino women and children of low socioeconomic status. Potential confounding factors from other environmental contaminants could not be ruled out. Associations of peripubertal measurements with parabens may reflect reverse causality because children going through puberty earlier may be more likely to use personal care products.
Parada et al. 2020 [20]. The highest (vs. lowest) quintiles of urinary MP, PP, and total parabens were associated with the risk of breast cancer. MP, PP, and total parabens were inversely associated with all-cause mortality hazard ratios. A case-control and follow up design. Large sample size. Participants included women with breast cancer and women without breast cancer. Among women with breast cancer, phenol biomarkers were quantified in urine samples. Women with breast cancer were monitored for vital status with a median follow-up of 17.6 years. Examined whether urinary phenol biomarkers were associated with mortality following breast cancer. A single spot urine sample may not be a reliable reflection of women’s parabens exposure. In addition, urine samples from breast cancer patients were collected after not before their diagnosis.
Wu et al. 2021 [21]. Breast cancer risk was weakly inversely associated with total (but not individual) parabens exposure. Risk of hormone receptor positive (HR+) cancer was lower among women in the upper two tertiles of paraben exposure. A multiethnic population-based nested case-control study. Examined the association between breast cancer risk and prediagnostic exposures paraben. Potential differences in terms of hormone receptor status, tumor stage (invasive vs in situ) and the length of follow-up time were considered in the analysis. All cases and controls were postmenopausal at the time of urine collection. A single measure of parabens to capture long-term exposures could lead to misclassification of exposure.

3. Estrogenic Effects of Parabens

Despite the limited epidemiological evidence linking paraben exposure with breast cancer, recent in vitro and animal studies have shed light on the endocrine-modulating effects of parabens, suggesting that parabens may be implicated in breast carcinogenesis.
Estrogen is the primary sex hormone responsible for mammary gland development during critical life stages [23][24]. The pubertal surge of secretion of estrogen and progesterone from the ovaries stimulates proliferation of the myoepithelial cells within ducts [25][26]. In addition, estrogen induces growth and branching of mammary ducts in cooperation with other growth factors by activating the estrogen receptors (ER) located in the epithelium and stromal cells [27][28][29].
The estrogenic activity of parabens has been well documented and characterized [2][10][30][31][32][33][34][35]. Parabens have been shown to regulate ER-mediated gene expression in vitro [2][30][31][32][33]. MP, EP, PP, BP, and BzP have an estradiol equivalence factor (EEF) of 1.25 × 10−7, 6.48 × 10−7, 2.39 × 10−6, 8.09 × 10−6, and 1.35 × 10−5 respectively [36]. In silico simulation has shown that MP and EP interact with the agonist-binding pocket of human ERα. MP and EP bound to Glu353 and Arg394 of human ER with binding energies of −49.35 and −53.38 kcal/mol, respectively. Both Glu353 and Arg394 are located at the ligand-binding pocket of the ER known to play a critical role in human ERα–17β-estradiol (E2) interaction [34]. The values of the negative binding energy indicate that the binding of parabens to ERα is likely to be a spontaneous process. The stimulatory effects on the proliferation of breast cancerous MCF-7 and noncancerous MCF-10A cells in response to either a single or repetitive exposure to MP, PP, or BP were studied [37]. While all tested parabens increased cell proliferation of MCF-7 cells, only MP and BP at low doses increased MCF-10A cells proliferation after a single exposure, but not repeated exposure. Moreover, MP, PP, and BP exposure at low doses significantly increased E2 secretion in MCF-7 cells, but they all had the opposite effect on MCF-10A cells [37]. Table 2 summarizes the differential effects of parabens on the gene expression of ER and progesterone receptor (PR) in MCF 7 vs. MCF-10 A cells [38]. Interesting, the effect of parabens on ERα and ERβ can be effectively blocked by ICI 182,780, the ER antagonist, in the MCF-7 cells [38]. In contrast, co-treatment with ICI 182,780 did not attenuate the stimulatory effect of parabens on either ERα or ERβ in the MCF-10A cells [38]. ERα and ERβ seem to play opposing roles in regulating growth and differentiation in response to estrogens in the breasts [39][40]. PR, an estrogen-regulated protein, is among the most important prognostic and predictive markers of response to endocrine therapies in breast cancer patients [41]. PR acts as a critical factor in the induction, progression, and maintenance of the neoplastic phenotype of ER-positive breast cancer [42]. Future studies are warranted to understand the biological implications of differential actions of parabens on ERs and PR in cancerous vs. noncancerous breast epithelial cells.
Table 2. Effect of 17β-estradiol (E2) and Parabens on Estrogen and Progesterone Receptors Gene and Protein Expression [38].
Table
  MCF-7
  ERα PR
  mRNA Protein mRNA Protein
  6 h 24 h 48 h 72 h 6 h 24 h 48 h 72 h
MP NC ↑ ↑ ↑ NC NC ↑ ↑
BP NC ↑ ↑ NC NC ↑ NC NC
PP NC ↑ ↑ NC NC ↑ ↑ ↑
E2 NC ↑ ↑ ↑ ↑ ↑ ↑ ↑
  MCF-10A
  ERα PR
  mRNA Protein mRNA Protein
  6 h 24 h 48 h 72 h 6 h 24 h 48 h 72 h
MP ↑ NC ↑ ↑ NC NC NC NC
BP NC NC NC NC NC ↑ NC NC
PP ↑ NC NC ↑ NC ↑ NC NC
E2 NC ↑ ↑ ↑ NC NC NC NC
  MCF-7 MCF-10A
  ERβ ERβ
  mRNA Protein mRNA Protein
  6 h 24 h 48 h 72 h 6 h 24 h 48 h 72 h
MP NC ↑ ↑ ↑ NC NC NC ↑
BP NC ↑ ↑ NC NC NC NC ↑
PP NC ↑ ↑ NC NC NC NC ↑
E2 NC ↑ ↑ ↑ NC NC NC NC
MCF-7 and MCF-10 A cells were exposed to parabens (20 nM) or E2 (10 nM); Gene expression was evaluated at 6 and 24 hours post treatment. Protein expression was evaluated at 48 and 72 hours post treatment. Up arrow: Upregulation; NC: No change.
The differential effect of parabens on the expression of genes related to cell cycle control and apoptosis has been investigated in MCF-7 and MCF-10A cells [43]. As shown in Table 3, these results further demonstrated variabilities in gene expression between cancerous and noncancerous breast epithelial cell lines in response to parabens. The discrepancy in cellular behavior between cancerous and noncancerous breast epithelia in response to parabens may suggest that parabens’ effects could be cell type-specific.
Table 3. Effect of 17-β Estradiol (E2) and Parabens on the Expression of Selected Genes in MCF-7 and MCF-10A [43].
Table
    MCF-7
  Genes CCND1 CCND3 CCNE1 CCNE2 CCNA2 CDK2 CDK4 CDK6 CDKN1A ATR ATM E2F3 TP53
E2   ↑ ↑ NC ↑ ↑ ↑ ↑ ↓ ↑ ↑ ↓ ↓ NC
MP   NC NC ↓ NC NC NC NC ↓ NC ↑ ↓ NC NC
PP   NC NC ↑ NC NC ↑ NC ↓ NC ↑ ↓ ↓ NC
BP   NC ↑ ↓ ↑ NC NC NC ↓ NC ↑ ↓ ↓ NC
    MCF-10A
  Genes CCND1 CCND3 CCNE1 CCNE2 CCNA2 CDK2 CDK4 CDK6 CDKN1A ATR ATM E2F3 TP53
E2   ↑ NC ↑ ↑ NC ↑ ↑ NC ↓ NC NC ↑ ↑
MP   ↑ NC ↑ NC ↑ ↑ ↑ ↓ ↓ NC NC ↑ NC
PP   ↑ ↓ ↑ NC ↑ ↑ ↑ NC ↓ NC ↑ ↑ ↑
BP   ↑ ↓ ↑ ↑ ↑ ↑ ↑ ↑ ↓ ↑ ↑ ↑ NC
MCF-7 and MCF-10A cells were exposed to MP, BP, and PP (20 nM) or E2 (10 nM) for 24 hours. Up arrow: Upregulation of gene expression; down arrow: Downregulation of gene expression; NC: Non change.
Global changes in gene expression profiles in response to parabens or E2 treatment have been studied in MCF-7 cells [44]. MCF-7 cells treated for 3 days with EP, PP, and BP, but not MP, showed gene expression profiles that correlated well with those genes in response to E2 treatment and the length of the alkyl chain of parabens was crucial for the estrogen-like profiles [44]. MCF-7 cells were also treated with 5 × 10−4 M MP, 10−5 M BP, or 10−8 M E2 for 7 days and the global gene expression profiles in response to the treatments were compared [45]. Of the 19,881 human genes investigated, 1972 genes were altered by ≥2-fold by MP, 1,292 genes were altered by ≥2-fold by BP, and 857 genes were altered ≥2-fold by E2. Only 61 genes were upregulated ≥2-fold by MP, BP and E2, while 198 genes were downregulated by ≥2-fold by all three test compounds [45]. Therefore, the majority of genes did not follow the same pattern of regulation by all three treatments in MCF-7 cells [45]. These results demonstrated that although parabens are estrogenic, their mimicry of E2 in global gene expression patterns is not perfect. Differences in gene expression profiles in cells in response to parabens could lead to different biological and developmental trajectories compared to the cells exposed to E2 [45].
In vivo studies of the effects of parabens on dynamic histological changes in mammary gland development have been studied in Sprague-Dawley rats [46]. Compared to the rats treated with the vehicle control, MP at doses that mimic human exposure levels during perinatal, prepuberty, and puberty significantly decreased amount of adipose tissue while increased expansion of the ductal tree and/or elevated amount of glandular tissue with a higher degree of branching. The authors identified puberty as the window of heightened sensitivity to MP, with increased glandular tissue and differential expression of 295 genes with significant enrichment of genes involved in DNA replication and cell cycle regulation [46]. It is worth noting that the genes modified by MP are also well represented in the gene signature profiles of human breast cancer, suggesting a possible link between MP exposure during the critical window of breast development and a higher risk of breast cancer [46].
In vivo studies of the effects of parabens on breast cancer initiation and progression are still scarce. In one study, MP at the levels that are commonly used in personal care products promoted the development of larger tumors than the placebo treatment in the nude mice xenografted with ER+ MCF-7 cells. Similarly, MP treatment significantly increased the volume of human patient-derived xenograft breast tumors compared to the placebo [47]. Additional in vivo studies using different breast cancer animal models are necessary to understand the full extent of the effects of parabens on breast cancer development.

4. Conclusions and Future Perspectives

Parabens are a group of EDCs commonly found in personal care products, foods, and pharmaceuticals. Systemic exposure to parabens has been confirmed by the ubiquitous detection of parabens in human blood and urine samples. The main concerns regarding parabens use in consumer products are their potential mimicry of endogenous hormones, possible cross-talks with other signal transduction pathways, such as HER2 signaling pathway, that are pivotal in the development of breast cancer, and modulation of key enzymes involved in local estrogen metabolism. Estrogen receptor is a key transcriptional factor that drives the oncogenesis and growth of hormonally sensitive breast cells. However, the recurrence and resistance to endocrine therapy of certain types of breast cancer, indicate that underlying mechanisms of breast cancer development are likely complex, involving multiple signaling pathways. Figure 1 highlights some possible mechanisms by which parabens affect breast cancer development.
/media/item_content/202202/621478642e085ijerph-19-01873-g001.pngFigure 1. Molecular mechanisms by which parabens act in breast cancer cells.
Although some research findings have suggested that parabens may negatively interfere with some endocrine targets relevant to breast carcinogenesis, evidence from in vivo and epidemiological studies linking paraben exposure to breast cancer is limited. So far, most studies have focused on one single paraben and/or the direct modulating effects of parabens on sex hormone receptors. Parabens are known to have significantly lower binding affinities to estrogen receptors than their endogenous counterparts. Therefore, the direct link of the estrogenic effect of parabens to breast carcinogenesis is debatable.
Future studies investigating paraben mixtures and their cross-talks with other EDCs or signaling pathways both in vivo and in vitro are warranted. For now, cautions should be taken when individuals, including breast cancer patients or individuals with high risk of breast cancer, make the decisions on personal care products containing parabens.

References

  1. ACS. About Breast Cancer. 2021. Available online: https://www.cancer.org/cancer/breast-cancer.html (accessed on 30 December 2021).
  2. Darbre, P.D. Environmental oestrogens, cosmetics and breast cancer. Best Pract. Res. Clin. Endocrinol. Metab. 2006, 20, 121–143.
  3. Ghosn, B.; Benisi-Kohansal, S.; Ebrahimpour-Koujan, S.; Azadbakht, L.; Esmaillzadeh, A. Association between healthy lifestyle score and breast cancer. Nutr. J. 2020, 19, 4.
  4. Rodgers, K.M.; Udesky, J.O.; Rudel, R.A.; Brody, J.G. Environmental chemicals and breast cancer: An updated review of epidemiological literature informed by biological mechanisms. Environ. Res. 2018, 160, 152–182.
  5. Darbre, P.D. Endocrine disrupting chemicals and breast cancer cells. Adv. Pharm. 2021, 92, 485–520.
  6. Wan, M.L.Y.; Co, V.A.; El-Nezami, H. Endocrine disrupting chemicals and breast cancer: A systematic review of epidemiological studies. Crit. Rev. Food Sci. Nutr. 2021, 5, 1–27, Online ahead of print.
  7. La Merrill, M.A.; Vandenberg, L.N.; Smith, M.T.; Goodson, W.; Browne, P.; Patisaul, H.B.; Guyton, K.Z.; Kortenkamp, A.; Cogliano, V.J.; Woodruff, T.J.; et al. Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat. Rev. Endocrinol. 2020, 16, 45–57.
  8. NIEHS. Endocrine Disruptors. 2021. Available online: https://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm (accessed on 30 December 2021).
  9. Nowak, K.; Ratajczak–Wrona, W.; Górska, M.; Jabłońska, E. Parabens and their effects on the endocrine system. Mol. Cell Endocrinol. 2018, 474, 238–251.
  10. Karpuzoglu, E.; Holladay, S.D.; Gogal, R.M., Jr. Parabens: Potential impact of low-affinity estrogen receptor binding chemicals on human health. J. Toxicol. Environ. Health B Crit. Rev. 2013, 16, 321–335.
  11. Karwacka, A.; Zamkowska, D.; Radwan, M.; Jurewicz, J. Exposure to modern, widespread environmental endocrine disrupting chemicals and their effect on the reproductive potential of women: An overview of current epidemiological evidence. Hum. Fertil. 2019, 22, 2–25.
  12. Harley, K.G.; Berger, K.P.; Kogut, K.; Parra, K.; Lustig, R.H.; Greenspan, L.C.; Calafat, A.M.; Ye, X.; Eskenazi, B. Association of phthalates, parabens and phenols found in personal care products with pubertal timing in girls and boys. Hum Reprod. 2019, 34, 109–117.
  13. Yager, J.D.; Davidson, N.E. Estrogen carcinogenesis in breast cancer. N. Engl. J. Med. 2006, 354, 270–282.
  14. Darbre, P.D.; Harvey, P.W. Parabens can enable hallmarks and characteristics of cancer in human breast epithelial cells: A review of the literature with reference to new exposure data and regulatory status. J. Appl. Toxicol. 2014, 34, 925–938.
  15. Barr, L.; Metaxas, G.; Harbach, C.A.; Savoy, L.A.; Darbre, P.D. Measurement of paraben concentrations in human breast tissue at serial locations across the breast from axilla to sternum. J. Appl. Toxicol. 2012, 32, 219–232.
  16. Darbre, P.D.; Aljarrah, A.; Miller, W.R.; Coldham, N.G.; Sauer, M.J.; Pope, G.S. Concentrations of parabens in human breast tumours. Concentrations of parabens in human breast tumours. J. Appl. Toxicol. 2004, 24, 5–13.
  17. Wang, L.; Asimakopoulos, A.G.; Kannan, K. Accumulation of 19 environmental phenolic and xenobiotic heterocyclic aromatic compounds in human adipose tissue. Environ. Int. 2015, 78, 45–50.
  18. Sprague, B.L.; Gangnon, R.E.; Burt, V.; Trentham-Dietz, A.; Hampton, J.M.; Wellman, R.D.; Kerlikowske, K.; Miglioretti, D.L. Prevalence of mammographically dense breasts in the United States. J. Natl. Cancer Inst. 2014, 106, 255.
  19. Sprague, B.L.; Trentham-Dietz, A.; Hedman, C.J.; Wang, J.; Hemming, J.D.; Hampton, J.M.; Buist, D.S.; Bowles, E.J.; Sisney, G.S.; Burnside, E.S. Circulating serum xenoestrogens and mammographic breast density. Breast Cancer Res. 2013, 15, R45.
  20. Parada, H., Jr.; Gammon, M.D.; Ettore, H.L.; Chen, J.; Calafat, A.M.; Neugut, A.I.; Santella, R.M.; Wolff, M.S.; Teitelbaum, S.L. Urinary concentrations of environmental phenols and their associations with breast cancer incidence and mortality following breast cancer. Environ. Int. 2019, 130, 104890.
  21. Wu, A.H.; Franke, A.A.; Wilkens, L.R.; Tseng, C.; Conroy, S.M.; Li, Y.; Sangaramoorthy, M.; Polfus, L.M.; DeRouen, M.C.; Caberto, C.; et al. Risk of breast cancer and prediagnostic urinary excretion of bisphenol A, triclosan and parabens: The Multiethnic Cohort Study. Int. J. Cancer 2021, 149, 1426–1434.
  22. Golden, R.; Gandy, J.; Vollmer, G. A review of the endocrine activity of parabens and implications for potential risks to human health. Crit. Rev. Toxicol. 2005, 35, 435–458.
  23. Fuentes, N.; Silveyra, P. Estrogen receptor signaling mechanisms. Adv. Protein Chem. Struct. Biol. 2019, 116, 135–170.
  24. Lee, H.R.; Kim, T.H.; Choi, K.C. Functions and physiological roles of two types of estrogen receptors, ERalpha and ERbeta, identified by estrogen receptor knockout mouse. Lab. Anim. Res. 2012, 28, 71–76.
  25. Arendt, L.M.; Kuperwasser, C. Form and function: How estrogen and progesterone regulate the mammary epithelial hierarchy. J. Mammary Gland. Biol. Neoplasia 2015, 20, 9–25.
  26. Russo, J.; Russo, I.H. Development of the human breast. Maturitas 2004, 49, 2–15.
  27. Hinck, L.; Silberstein, G.B. Key stages in mammary gland development: The mammary end bud as a motile organ. Breast Cancer Res. 2005, 7, 245–251.
  28. Silberstein, G.B. Tumour-stromal interactions. Role of the stroma in mammary development. Breast Cancer Res. 2001, 3, 218–223.
  29. Javed, A.; Lteif, A. Development of the human breast. Semin. Plast. Surg. 2013, 27, 5–12.
  30. Darbre, P.D.; Byford, J.R.; Shaw, L.E.; Hall, S.; Coldham, N.G.; Pope, G.S.; Sauer, M.J. Oestrogenic activity of benzylparaben. J. Appl. Toxicol. 2003, 23, 43–51.
  31. Darbre, P.D.; Byford, J.R.; Shaw, L.E.; Horton, R.A.; Pope, G.S.; Sauer, M.J. Oestrogenic activity of isobutylparaben in vitro and in vivo. J. Appl Toxicol. 2002, 22, 219–226.
  32. Darbre, P.D.; Harvey, P.W. Paraben esters: Review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. J. Appl. Toxicol. 2008, 28, 561–578.
  33. Lemini, C.; Jaimez, R.; Avila, M.E.; Franco, Y.; Larrea, F.; Lemus, A.E. In vivo and in vitro estrogen bioactivities of alkyl parabens. Toxicol. Ind. Health 2003, 19, 69–79.
  34. Sun, L.; Yu, T.; Guo, J.; Zhang, Z.; Hu, Y.; Xiao, X.; Sun, Y.; Xiao, H.; Li, J.; Zhu, D.; et al. The estrogenicity of methylparaben and ethylparaben at doses close to the acceptable daily intake in immature Sprague-Dawley rats. Sci. Rep. 2016, 6, 25173.
  35. Vo, T.T.; Yoo, Y.M.; Choi, K.C.; Jeung, E.B. Potential estrogenic effect(s) of parabens at the prepubertal stage of a postnatal female rat model. Reprod. Toxicol. 2010, 29, 306–316.
  36. Lange, C.; Kuch, B.; Metzger, J.W. Estrogenic activity of constituents of underarm deodorants determined by E-Screen assay. Chemosphere 2014, 108, 101–106.
  37. Wrobel, A.; Gregoraszczuk, E.L. Effects of single and repeated in vitro exposure of three forms of parabens, methyl-, butyl- and propylparabens on the proliferation and estradiol secretion in MCF-7 and MCF-10A cells. Pharm. Rep. 2013, 65, 484–493.
  38. Wrobel, A.M.; Gregoraszczuk, E.L. Actions of methyl-, propyl- and butylparaben on estrogen receptor-alpha and -beta and the progesterone receptor in MCF-7 cancer cells and non-cancerous MCF-10A cells. Toxicol. Lett. 2014, 230, 375–381.
  39. Dall, G.V.; Hawthorne, S.; Seyed-Razavi, Y.; Vieusseux, J.; Wu, W.; Gustafsson, J.A.; Byrne, D.; Murphy, L.; Risbridger, G.P.; Britt, K.L. Estrogen receptor subtypes dictate the proliferative nature of the mammary gland. J. Endocrinol. 2018, 237, 323–336.
  40. Treeck, O.; Lattrich, C.; Springwald, A.; Ortmann, O. Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells. Breast Cancer Res. Treat. 2010, 120, 557–565.
  41. Kunc, M.; Biernat, W.; Senkus-Konefka, E. Estrogen receptor-negative progesterone receptor-positive breast cancer–”Nobody’s land” or just an artifact? Cancer Treat. Rev. 2018, 67, 78–87.
  42. Lanari, C.; Molinolo, A.A. Progesterone receptors–Animal models and cell signalling in breast cancer. Diverse activation pathways for the progesterone receptor: Possible implications for breast biology and cancer. Breast Cancer Res. 2002, 4, 240–243.
  43. Wrobel, A.M.; Gregoraszczuk, E.L. Differential effect of methyl-, butyl- and propylparaben and 17beta-estradiol on selected cell cycle and apoptosis gene and protein expression in MCF-7 breast cancer cells and MCF-10A non-malignant cells. J. Appl. Toxicol. 2014, 34, 1041–1050.
  44. Terasaka, S.; Inoue, A.; Tanji, M.; Kiyama, R. Expression profiling of estrogen-responsive genes in breast cancer cells treated with alkylphenols, chlorinated phenols, parabens, or bis- and benzoylphenols for evaluation of estrogenic activity. Toxicol. Lett. 2006, 163, 130–141.
  45. Pugazhendhi, D.; Sadler, A.J.; Darbre, P.D. Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J. Appl. Toxicol. 2007, 27, 67–77.
  46. Gopalakrishnan, K.; Teitelbaum, S.L.; Lambertini, L.; Wetmur, J.; Manservisi, F.; Falcioni, L.; Panzacchi, S.; Belpoggi, F.; Chen, J. Changes in mammary histology and transcriptome profiles by low-dose exposure to environmental phenols at critical windows of development. Environ. Res. 2017, 152, 233–243.
  47. Lillo, M.A.; Nichols, C.; Perry, C.; Runke, S.; Krutilina, R.; Seagroves, T.N.; Miranda-Carboni, G.A.; Krum, S.A. Methylparaben stimulates tumor initiating cells in ER+ breast cancer models. J. Appl. Toxicol. 2017, 37, 417–425.
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Subjects: Endocrinology & Metabolism
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Jiangang Chen
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