Alcohol Promotes ER+ Breast Cancer Cell Proliferation and Invasion Through the Upregulation of Neuregulin 1-Mediated ER-ErbB3 Crosstalk
Alcohol consumption is an established risk factor for breast cancer, with a particularly strong association with estrogen receptor-positive (ER+) disease. Although the estrogenic activity of alcohol is well recognized, how alcohol-induced ER signaling is coupled to growth factor receptor pathways that promote tumor cell growth and progression remains incompletely understood. Here, we identify…
Alcohol consumption is linked to a heightened risk of developing breast cancer, with a stronger connection to estrogen receptor-positive (ER+) cases. While the estrogenic effects of alcohol are well-known, the relationship between alcohol-induced ER signaling and growth factor receptor pathways in tumor cell proliferation and progression is still not fully understood.
In this study, researchers discovered that neuregulin-1 (NRG1) plays a crucial role in linking alcohol-induced ER activity to ErbB3 receptor tyrosine kinase signaling in ER+ breast cancer cells. When estrogen levels are low, alcohol consumption leads to increased proliferation, clonogenic growth, and progression into the S-phase in MCF-7 and T47D cells.
Additionally, alcohol consumption boosts ER phosphorylation, transcriptional activity, and the activation of ErbB3 and downstream signaling pathways such as Akt, ERK, and p38. Furthermore, alcohol triggers the expression of NRG1 in both cell lines. Inhibiting ER signaling with ICI 182,780 (fulvestrant) significantly reduced NRG1 induction, ErbB3/RTK activation, and alcohol-promoted growth, suggesting that NRG1 induction and RTK signaling engagement heavily rely on functional ER signaling.
Conversely, reducing NRG1 levels using shRNA inhibited alcohol-induced proliferation, clonogenic growth, and cell-cycle progression, while also lessening alcohol-induced migration and invasion. NRG1 depletion also diminished ErbB3/Akt/ERK signaling and decreased ER activation, indicating its essential role in both parts of the signaling response.
Overall, these results demonstrate a reciprocal ER-NRG1-ErbB3 signaling circuit where alcohol-induced ER activity triggers NRG1 expression, and NRG1-mediated ErbB3 signaling reinforces ER activity and cancer-promoting features. This research identifies NRG1 as a previously unknown molecular connection between alcohol's estrogenic effects and growth factor receptor signaling, offering a mechanistic explanation for alcohol's contribution to ER+ breast cancer promotion.
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