PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects
<p>The PI3K/AKT/mTOR signaling pathway. PI3K is activated by the binding of ligands (insulin, growth factors, hormones) to RTKs, but also to GPCR (chemokines). Once activated, this protein kinase will catalyze the phosphorylation of PIP2 to PIP3. AKT is recruited to the plasma membrane where it undergoes two phosphorylation processes, one catalyzed by PDK1 at the level of threonine residue and the second reaction being catalyzed by mTORC2. Once activated by phosphorylation, AKT will phosphorylate other substances such as the mTOR complex, which will be associated in the end with protein synthesis and cell growth. Other phosphorylated substrates, such as GSK-3 and Fox01, will be inhibited, associated with cell proliferation and survival. PTEN is the major negative regulator of this signaling pathway involved in PIP3 dephosphorylation.</p> "> Figure 2
<p>The PI3K/AKT/mTOR signaling pathway and breast cancer. The PI3K/AKT/mTOR signaling pathway is activated by ER, but also by EGFR, HER 2, IGFR1R, and FGFR1 at RTKs level. Once activated, protein kinase B or AKT inhibits TSC ½ by phosphorylation, further leading to the inhibition of Rheb and activation of mTORC1. This activation is associated with anti-apoptotic effects, increased gene expression, cell proliferation and angiogenesis. Everolimus and temsirolimus are two analogues of rapamycin that inhibit the activity of mTOR, especially mTORC1, but also mTORC2.</p> ">
Abstract
:1. Breast Cancer–Incidence and Risk Factors
2. Molecular Types of Breast Cancer
- ER-estrogen receptor status.
- PR-progesterone receptor status.
- Note that HR-represents the joint assessment of ER and PR status.
- 3.
- HER2-human epidermal growth factor receptor 2 status.
- HR+/HER2– corresponding to Luminal A subtype.
- HR+/HER2+ corresponding to Luminal B subtype.
- HR−/HER2+ corresponding to HER2 enriched subtype.
- HR−/HER2– corresponding to triple negative subtype.
3. PI3K/AKT/mTOR Signaling Pathway
3.1. PI3K/AKT/mTOR Signaling Pathway Members
3.1.1. PI3K-Phosphatidylinositol 3-Kinase-(Phosphoinositide 3-Kinase)
3.1.2. AKT
3.1.3. mTOR
3.1.4. FoxO1
3.1.5. PTEN
4. PI3K/AKT/mTOR Mutations in Breast Cancer
HER Receptors and Breast Cancers
5. Mechanisms of Endocrine Resistance in Breast Cancer
6. mTOR Inhibitors: Everolimus and Temsirolimus
7. Conclusions
Funding
Conflicts of Interest
References
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mTOR Inhibitors | Type of Breast Cancer | Type of Study | References |
---|---|---|---|
Everolimus + exemestane | hormone-receptor-positive advanced breast cancer | Phase 3, randomized trial | [180] |
Everolimus + fulvestrant | estrogen receptor-positive breast cancer | Phase 2 Manta trial | [181] |
Everolimus + tamoxifen | metastatic breast cancer | Phase II Randomized trial | [182] |
Everolimus + plustrastuzumab + vinorelbine | HER2-positive breast cancer | Phase 3 trial (Bolero-3) | [183] |
Everolimus + trastuzumab + paclitaxel | HER2-positive advanced breast cancer | Phase 2 multicenter study | [184] |
Everolimus | metastatic breast cancer | Retrospective study | [186] |
Temsirolimus + letrozole | hormone receptor-positive metastatic breast cancer | Phase III randomized trial | [188] |
Temsirolimus | metastatic breast cancer | Phase II trial | [189] |
Sirolimus + Tamoxifen | hormone receptor-positive and HER2-negative breast cancer | Phase I/II trial | [191] |
Ridaforolimus + trastuzumab | Human epidermal growth factor receptor 2–positive (HER2+) trastuzumab-refractory metastatic breast cancer | Phase IIb trail | [192] |
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Miricescu, D.; Totan, A.; Stanescu-Spinu, I.-I.; Badoiu, S.C.; Stefani, C.; Greabu, M. PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects. Int. J. Mol. Sci. 2021, 22, 173. https://doi.org/10.3390/ijms22010173
Miricescu D, Totan A, Stanescu-Spinu I-I, Badoiu SC, Stefani C, Greabu M. PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects. International Journal of Molecular Sciences. 2021; 22(1):173. https://doi.org/10.3390/ijms22010173
Chicago/Turabian StyleMiricescu, Daniela, Alexandra Totan, Iulia-Ioana Stanescu-Spinu, Silviu Constantin Badoiu, Constantin Stefani, and Maria Greabu. 2021. "PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects" International Journal of Molecular Sciences 22, no. 1: 173. https://doi.org/10.3390/ijms22010173