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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
Estrogen suppresses MLK3-mediated apoptosis sensitivity in ER+ breast cancer cells
Velusamy Rangasamy1, Rajakishore Mishra, Suneet Mehrotra
1Department of Pharmacology, Loyola University Chicago, Maywood, Illinois 60153, USA.
Abstract:
Little knowledge exists about the mechanisms by which estrogen can impede chemotherapy-induced cell death of breast cancer cells. 17beta-Estradiol (E(2)) hinders cytotoxic drug-induced cell death in estrogen receptor-positive (ER(+)) breast cancer cells. We noted that the activity of the proapoptotic mixed lineage kinase 3 (MLK3) kinase was relatively higher in estrogen receptor-negative (ER(-)) breast tumors, suggesting that E(2) might inhibit MLK3 activity. The kinase activities of MLK3 and its downstream target, c-Jun NH(2)-terminal kinase, were rapidly inhibited by E(2) in ER(+) but not in ER(-) cells. Specific knockdown of AKT1/2 prevented MLK3 inhibition by E(2), indicating that AKT mediated this event. Furthermore, MLK3 inhibition by E(2) involved phosphorylation of MLK3 Ser(674) by AKT, attenuating the proapoptotic function of MLK3. We found that a pan-MLK inhibitor (CEP-11004) limited Taxol-induced cell death and that E(2) accentuated this limitation. Taken together, our findings indicate that E(2) inhibits the proapoptotic function of MLK3 as a mechanism to limit cytotoxic drug-induced death of ER(+) breast cancer cells.
Insights
Estrogen (E(2)) hinders chemotherapy effectiveness in estrogen receptor-positive (ER(+)) breast cancer by inhibiting the proapoptotic kinase MLK3. This estrogen-mediated inhibition of MLK3 reduces cancer cell death, impacting treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Estrogen (E(2)) is known to affect breast cancer cell proliferation and survival.
- The precise mechanisms by which E(2) influences chemotherapy resistance in estrogen receptor-positive (ER(+)) breast cancer remain incompletely understood.
- Mixed lineage kinase 3 (MLK3) is a proapoptotic kinase whose activity may be modulated by estrogen.
Purpose of the Study:
- To investigate the role of estrogen in mediating resistance to chemotherapy-induced cell death in ER(+) breast cancer.
- To elucidate the molecular mechanisms underlying estrogen's effect on apoptosis pathways.
- To determine if MLK3 is a target of estrogen action in breast cancer cells.
Main Methods:
- Western blotting to assess kinase activity and phosphorylation.
- RNA interference (siRNA) to knockdown specific genes (e.g., AKT1/2).
- Treatment with 17beta-estradiol (E(2)), cytotoxic drugs (Taxol), and MLK inhibitors (CEP-11004).
- Cell viability assays to measure chemotherapy-induced cell death.
Main Results:
- Estrogen (E(2)) rapidly inhibited MLK3 and c-Jun NH(2)-terminal kinase activity in ER(+) breast cancer cells, but not in ER(-) cells.
- Knockdown of AKT1/2 prevented E(2)-mediated inhibition of MLK3, identifying AKT as a mediator.
- E(2) inhibited MLK3 via AKT-mediated phosphorylation at Ser(674), attenuating MLK3's proapoptotic function.
- A pan-MLK inhibitor limited Taxol-induced cell death, an effect accentuated by E(2).
Conclusions:
- Estrogen (E(2)) inhibits the proapoptotic function of MLK3 in ER(+) breast cancer cells.
- This inhibition is mediated by the AKT signaling pathway, involving phosphorylation of MLK3.
- Estrogen's suppression of MLK3 represents a mechanism by which ER(+) breast cancer cells resist chemotherapy-induced death.
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