Abstract
Over 70% of breast cancers are estrogen receptor (ER)-positive, with Tamoxifen (Tam) being a standard treatment. However, around 40% of these cancers develop resistance to Tam, which poses a significant clinical challenge. The ACOD1/itaconate (ITA) axis, a metabolic pathway that produces itaconate, has shown promise in inhibiting the growth of ER-positive breast cancer cells. Nonetheless, it remains unclear how effective ITA is against Tam-resistant breast cancer cells and the underlying mechanisms involved. The current report found that Tam-resistant cells exhibit increased sensitivity to ITA compared to their parental cells and show a synergetic effect in combination treatment with Tam. An unbiased proteomic analysis revealed that upregulating the ERK2 signaling pathway contributes to the sensitivity of ER-positive breast cancer cells to ITA. ITA treatment increases ERK2 phosphorylation at T185/Y187 sites by directly alkylating cysteine 254, leading to ERK2 activation and subsequent cell growth inhibition. These effects were abolished in ITA allylation-resistant cells when a cysteine residue was replaced with serine. Additionally, itaconate-induced ERK2 phosphorylation and activation inhibits the growth of Tam-resistant breast cancer cells, which effect is advanced in phosphorylation-mimic ERK2_T185E-expressing cells but blocked in those expressing non-phosphorylation-mimic ERK2_T185A. Furthermore, activated ERK2 interacts physically with API5 to disrupt API5's localization to the nucleus speckle, where API5 may interact with other molecules critical in regulating cell growth-related genes. Our findings clarify the mechanism through which ITA exerts its effects on tamoxifen-sensitive and resistant breast cancer cells and highlight the potential of itaconate as an alternative treatment strategy against breast cancer.
Keywords:
Aconitate decarboxylase 1; breast cancer; estrogen receptor; extracellular signal-regulated kinase 2; itaconate; tamoxifen.