Signal Transduction Pathways in Breast Cancer: The Important Role of PI3K/Akt/mTOR

Abstract

Breast cancer is the cancer with the highest prevalence in women and is the number-one cause of cancer mortality worldwide. Cell transduction is a fundamental process in the development and progression of cancer. Modifications in various cell signalling pathways promote tumour cell proliferation, progression, and survival. The PI3K/Akt/mTOR pathway is an example of that, and it is involved in growth, proliferation, survival, motility, metabolism, and immune response regulation. Activation of this pathway is one of the main causes of cancer cell resistance to antitumour therapies. This makes PI3K/Akt/mTOR signalling a crucial object of study for understanding the development and progression of this disease. Thus, this pathway may have a role as a potential therapeutic target, as well as prognostic and diagnostic value, in patients with breast cancer. Despite the existence of selective PI3K/Akt/mTOR pathway inhibitors and current clinical trials, the cellular mechanisms are not yet known. The present review aims to understand the current state of this important disease and the paths that must be forged.

Figure 1

Overview of cell signalling mediated by the tyrosine kinase receptors (RTKs) Her2/Neu and estrogen receptors (ERs), two key components of breast cancer development. Their activation initiates the PI3K/Akt/mTOR and MAPK pathways, finally promoting cell growth, proliferation, survival, and other hallmarks of cancer. Although this is a review of PI3K/Akt/mTOR signalling, it is important to understand that the different pathways are connected by different points. In this figure, we have presented two examples: Ras, promoting PI3K activation, and how some AGC kinases (such as SGK-3) activated by mTORC2 also interact with the MAPK pathway. Additionally, GSK-3 plays an important role as well in the regulation of these pathways, represented in the figure. GSK-3 is an example of how complex those interactions are, by the inhibition and activation of different molecules implicated in PI3K and MAPK pathways.

Figure 2

Mechanism of action of PI3K and PTEN. RTK receptors are activated, phosphorylating themselves and other series of adapter proteins, such as IRS-1. In this case, the regulatory subunit p85 binds to these residues and releases the catalytic subunit p110α, which adds a phosphate to PIP2 and transforms it into PIP3, which will subsequently activate Akt. PTEN prevents this activation by dephosphorylating PIP3. The loss of function of this gene, represented in red, or activating PI3KCA mutations, shown in green, can overactivate this route, favouring the development of cancer.

Figure 3

Activation of Akt after joining to PIP3 by its PH domain. PDK1 and PDK2, present in mTORC2, phosphorylate Akt, which will activate and inhibit a series of genes, transcription factors, and proteins, represented in red, such as the TSC complex, which will eventually activate mTORC1, resulting in a series of cellular responses. We have remarked in green the components which are stimulated or overactive in these cells. This figure also shows the main therapies developed to focus on this pathway.