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Updated: Aug 13, 2026
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An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
Published on: June 30, 2015
Isoform-Specific Modulation of PI3K/Akt1 Signaling by Orai Channels in Estrogen Receptor-Positive Breast Cancer
Alvaro Macías-Díaz1, Jose J Lopez1, Manuel Fuentes-Mateos1
1Department of Physiology (Cellular Physiology Research Group), Institute of Molecular Pathology Biomarkers (IMPB), Universidad de Extremadura, 10003-Caceres, Spain.
American Journal of Physiology. Cell Physiology
|August 11, 2026
Summary
Orai1 and Orai3 channels have opposing roles in estrogen receptor-positive breast cancer. Orai3 promotes Akt1 activation, while Orai1 inhibits it, revealing distinct signaling pathways influencing cancer aggressiveness.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is crucial for cellular processes and cancer progression.
- Akt1 activation is linked to aggressiveness in estrogen receptor-positive (ER+) breast cancer.
- Calcium (Ca2+) signaling, particularly through Orai1 and Orai3 channels, is implicated in ER+ breast cancer.
Purpose of the Study:
- To investigate the regulation of Akt1 activation by Orai3 and Orai1 in ER+ breast cancer cells.
- To characterize the underlying intracellular mechanisms of Orai1 and Orai3 in modulating Akt1 activity.
Main Methods:
- Utilized Orai1-knockout (O1KO) and wild-type MCF-7 cells.
- Employed Orai3 overexpression and knockdown strategies.
- Investigated the role of 2-APB, calmodulin-dependent protein kinase kinase (CaMKK), and adenylyl cyclase 8 (AC8).
- Assessed Akt1 phosphorylation and AC8 expression levels.
Main Results:
- Orai3 overexpression and Orai1 stimulation (via 2-APB in O1KO cells) enhanced Akt1 phosphorylation.
- Orai3 knockdown attenuated Akt1 phosphorylation.
- Orai1 deficiency (O1KO or knockdown) increased Akt1 phosphorylation, while Orai1 overexpression decreased it.
- Ca2+ influx via Orai1 is essential for Akt modulation.
- Orai1 regulates Akt phosphorylation through modulation of adenylyl cyclase 8 (AC8) expression.
Conclusions:
- Orai1 and Orai3 exhibit opposing roles in regulating Akt1 phosphorylation in ER+ breast cancer cells.
- Orai3 promotes Akt1 activation, potentially via CaMKK-dependent pathways.
- Orai1 inhibits Akt1 activation through a Ca2+-dependent mechanism involving AC8.
- These findings reveal a novel functional antagonism between Orai1 and Orai3 impacting ER+ breast cancer signaling.
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