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Endocrine disruptor regulation of microRNA expression in breast carcinoma cells.

Tilghman SL, Bratton MR, Segar HC, Martin EC, Rhodes LV, Li M, McLachlan JA, Wiese TE, Nephew KP, Burow ME - PLoS ONE (2012)

Bottom Line: Given the important implications of EDC-regulated ER function, we sought to define the effects of BPA and DDT on microRNA regulation and expression levels in estrogen-responsive human breast cancer cells.To investigate the cellular effects of DDT and BPA, we used the human MCF-7 breast cancer cell line, which is ER (+) and hormone sensitive.Our results show that DDT and BPA potentiate ER transcriptional activity, resulting in an increased expression of receptor target genes, including progesterone receptor, bcl-2, and trefoil factor 1.

View Article: PubMed Central - PubMed

Affiliation: Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.

ABSTRACT

Background: Several environmental agents termed "endocrine disrupting compounds" or EDCs have been reported to bind and activate the estrogen receptor-α (ER). The EDCs DDT and BPA are ubiquitously present in the environment, and DDT and BPA levels in human blood and adipose tissue are detectable in most if not all women and men. ER-mediated biological responses can be regulated at numerous levels, including expression of coding RNAs (mRNAs) and more recently non-coding RNAs (ncRNAs). Of the ncRNAs, microRNAs have emerged as a target of estrogen signaling. Given the important implications of EDC-regulated ER function, we sought to define the effects of BPA and DDT on microRNA regulation and expression levels in estrogen-responsive human breast cancer cells.

Methodology/principal findings: To investigate the cellular effects of DDT and BPA, we used the human MCF-7 breast cancer cell line, which is ER (+) and hormone sensitive. Our results show that DDT and BPA potentiate ER transcriptional activity, resulting in an increased expression of receptor target genes, including progesterone receptor, bcl-2, and trefoil factor 1. Interestingly, a differential increase in expression of Jun and Fas by BPA but not DDT or estrogen was observed. In addition to ER responsive mRNAs, we investigated the ability of DDT and BPA to alter the miRNA profiles in MCF-7 cells. While the EDCs and estrogen similarly altered the expression of multiple microRNAs in MCF-7 cells, including miR-21, differential patterns of microRNA expression were induced by DDT and BPA compared to estrogen.

Conclusions/significance: We have shown, for the first time, that BPA and DDT, two well known EDCs, alter the expression profiles of microRNA in MCF-7 breast cancer cells. A better understanding of the molecular mechanisms of these compounds could provide important insight into the role of EDCs in human disease, including breast cancer.

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Related in: MedlinePlus

The effect of BPA and DDT on endogenous miR-21 target genes in MCF-7 cells.MCF-7 cells were treated for 18 hrs. with 0, 1, 10 and 25 µM BPA or DDT followed by RT-PCR of PDCD4 and maspin.
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pone-0032754-g006: The effect of BPA and DDT on endogenous miR-21 target genes in MCF-7 cells.MCF-7 cells were treated for 18 hrs. with 0, 1, 10 and 25 µM BPA or DDT followed by RT-PCR of PDCD4 and maspin.

Mentions: Previous studies have identified programmed cell death 4 (neoplastic transformation inhibitor) (PDCD4) and maspin as direct targets of miR-21 [38]. PDCD4 is a putative target of miR-21 and is implicated in the metastatic potential of pancreatic tumors [39], and maspin is a well-known tumor suppressor that can suppress tumor growth, invasion and metastasis [40]. Since E2, BPA and DDT reduced miR-21expression in MCF-7 cells, it was of interest to examine whether the effect of BPA and DDT resulted in altered expression of the two miR-21 target genes. MCF-7 cells were treated with increasing concentrations of BPA and DDT, and expression of maspin and PDCD4 was examined by RT-PCR. Results demonstrate a dose dependent increase in the expression of maspin and PDCD4 by BPA and DDT (Figure 6), suggesting that inhibition of miR-21 by DDT or BPA resulted in the increased expression of these two miR-21 target mRNAs. Interestingly, maspin appeared to be more sensitive to BPA and DDT than PDCD4 (Figure 6).


Endocrine disruptor regulation of microRNA expression in breast carcinoma cells.

Tilghman SL, Bratton MR, Segar HC, Martin EC, Rhodes LV, Li M, McLachlan JA, Wiese TE, Nephew KP, Burow ME - PLoS ONE (2012)

The effect of BPA and DDT on endogenous miR-21 target genes in MCF-7 cells.MCF-7 cells were treated for 18 hrs. with 0, 1, 10 and 25 µM BPA or DDT followed by RT-PCR of PDCD4 and maspin.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293845&req=5

pone-0032754-g006: The effect of BPA and DDT on endogenous miR-21 target genes in MCF-7 cells.MCF-7 cells were treated for 18 hrs. with 0, 1, 10 and 25 µM BPA or DDT followed by RT-PCR of PDCD4 and maspin.
Mentions: Previous studies have identified programmed cell death 4 (neoplastic transformation inhibitor) (PDCD4) and maspin as direct targets of miR-21 [38]. PDCD4 is a putative target of miR-21 and is implicated in the metastatic potential of pancreatic tumors [39], and maspin is a well-known tumor suppressor that can suppress tumor growth, invasion and metastasis [40]. Since E2, BPA and DDT reduced miR-21expression in MCF-7 cells, it was of interest to examine whether the effect of BPA and DDT resulted in altered expression of the two miR-21 target genes. MCF-7 cells were treated with increasing concentrations of BPA and DDT, and expression of maspin and PDCD4 was examined by RT-PCR. Results demonstrate a dose dependent increase in the expression of maspin and PDCD4 by BPA and DDT (Figure 6), suggesting that inhibition of miR-21 by DDT or BPA resulted in the increased expression of these two miR-21 target mRNAs. Interestingly, maspin appeared to be more sensitive to BPA and DDT than PDCD4 (Figure 6).

Bottom Line: Given the important implications of EDC-regulated ER function, we sought to define the effects of BPA and DDT on microRNA regulation and expression levels in estrogen-responsive human breast cancer cells.To investigate the cellular effects of DDT and BPA, we used the human MCF-7 breast cancer cell line, which is ER (+) and hormone sensitive.Our results show that DDT and BPA potentiate ER transcriptional activity, resulting in an increased expression of receptor target genes, including progesterone receptor, bcl-2, and trefoil factor 1.

View Article: PubMed Central - PubMed

Affiliation: Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.

ABSTRACT

Background: Several environmental agents termed "endocrine disrupting compounds" or EDCs have been reported to bind and activate the estrogen receptor-α (ER). The EDCs DDT and BPA are ubiquitously present in the environment, and DDT and BPA levels in human blood and adipose tissue are detectable in most if not all women and men. ER-mediated biological responses can be regulated at numerous levels, including expression of coding RNAs (mRNAs) and more recently non-coding RNAs (ncRNAs). Of the ncRNAs, microRNAs have emerged as a target of estrogen signaling. Given the important implications of EDC-regulated ER function, we sought to define the effects of BPA and DDT on microRNA regulation and expression levels in estrogen-responsive human breast cancer cells.

Methodology/principal findings: To investigate the cellular effects of DDT and BPA, we used the human MCF-7 breast cancer cell line, which is ER (+) and hormone sensitive. Our results show that DDT and BPA potentiate ER transcriptional activity, resulting in an increased expression of receptor target genes, including progesterone receptor, bcl-2, and trefoil factor 1. Interestingly, a differential increase in expression of Jun and Fas by BPA but not DDT or estrogen was observed. In addition to ER responsive mRNAs, we investigated the ability of DDT and BPA to alter the miRNA profiles in MCF-7 cells. While the EDCs and estrogen similarly altered the expression of multiple microRNAs in MCF-7 cells, including miR-21, differential patterns of microRNA expression were induced by DDT and BPA compared to estrogen.

Conclusions/significance: We have shown, for the first time, that BPA and DDT, two well known EDCs, alter the expression profiles of microRNA in MCF-7 breast cancer cells. A better understanding of the molecular mechanisms of these compounds could provide important insight into the role of EDCs in human disease, including breast cancer.

Show MeSH
Related in: MedlinePlus