Abstract: FRI 123

Methylparaben Increases Nanog Expression in Breast Cancer Stem Cells

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Abstract


Parabens (esters of p-hydroxybenzoic acid) are used as preservatives in personal care products. They are absorbed systemically from dermal application and can be endocrine disruptors. The measurement of parabens in human breast tissue and breast tumors and the estrogenic activity of parabens, combined with the known influence of estrogen on the development of breast cancer, has suggested that parabens might play a functional role in influencing the development of breast cancer. view more

Parabens (esters of p-hydroxybenzoic acid) are used as preservatives in personal care products. They are absorbed systemically from dermal application and can be endocrine disruptors. The measurement of parabens in human breast tissue and breast tumors and the estrogenic activity of parabens, combined with the known influence of estrogen on the development of breast cancer, has suggested that parabens might play a functional role in influencing the development of breast cancer. We therefore investigated the effect of Methylparaben (MePB), which is one of the highest parabens found in the breast, in estrogen receptor positive (ER+) breast tumor development. In vivo, MCF7 (ER+ human breast cancer cell line cells) and HCI-7 (ER+ breast tumor patient-derived tumor xenograft) injected into mice by subcutaneous transplantation or mammary fad pad transplantation developed bigger tumors in mice with MePB pellets than in mice with placebo pellets. However, in vitro, 10 nM MePB failed to increase the MCF7 cell number, in contrast to 10 nM E2, which increased the cell number of MCF7 cells 7 fold after one week. This concentration of MePB also failed to induce expression of the canonical estrogen responsive genes pS2 or PR genes in MCF7 cells. MePB induced ALDH1 expression, which is a marker of human mammary stem cells. In order to determine the effect of MePB on MCF7 breast cancer stem cells, and knowing that MCF7 mammospheres have been shown to enrich for breast cancer stem cells, MCF7 mammospheres were treated with 10 nM MePB. After 8 days in culture it was observed that these mammospheres were bigger than mammospheres not treated (EtOH) or treated with 10 nM E2 or 10 nM BPA. The increase in mammosphere size did not affect stem cells self-renewal capacity since mammosphere cells were able to form secondary mammospheres through repeated subculture. 10 nM mePB did not induce classical E2-responsive genes in MCF7 mammospheres cells, however, it did increase the expression of the stem cell markers Nanog, Oct4 and ALDH1. Furthermore, Nanog protein is upregulated by MePB. Nanog protein was observed in MCF7 xenograft tumors developed in mice with MePB pellet while the tumors that developed in mice with placebo pellet did not express Nanog protein. 10 nM MePB did not have any effect in MDA-MB-231 (breast cancer triple negative cell line) mammosphere size or Nanog expression. However, MePB’s increase in mammosphere size was not blocked by the pure anti-estrogen ICI182780 or Tamoxifen. Together, these results suggest that mePB increases breast cancer tumor formation and mammosphere stem cell size via regulation of Nanog.

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