The role of ERα36 in regulating BPA’s effects and its
potential as a risk factor for human uterine fibroids were evaluated. BPA at low
concentrations (10−6 μM - 10 μM) increased
proliferation by facilitating progression of hormonally regulated, immortalized
human uterine leiomyoma (ht-UtLM; fibroid) cells from
G0-G1 into S phase of the cell cycle; whereas, higher
concentrations (100 μM – 200 μM) decreased growth. BPA
upregulated ERα36 gene and protein expression, and induced increased SOS1
and Grb2 protein expression, both of which are mediators of the
MAPKp44/42/ERK1/2 pathway. EGFR (pEGFR), Ras, and
MAPKp44/42 were phosphorylated with concurrent Src activation in
ht-UtLM cells within 10 minutes of BPA exposure. BPA enhanced colocalization of
phosphorylated Src (pSrc) to ERα36 and coimmunoprecipitation of pSrc with
pEGFR. Silencing ERα36 with siERα36 abolished the above effects.
BPA induced proliferation in ht-UtLM cells through membrane-associated
ERα36 with activation of Src, EGFR, Ras and MAPK nongenomic signaling
pathways.
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