The most recurrent cause of cancer-related deaths worldwide in women is the breast cancer. The key to diagnosis is early prediction and a curable stage but still treatment remains a great clinical challenge. Origin of the Problem: A number of studies have been carried out for the treatment of breast cancer which includes the targeted therapies and increased survival rates in women. Essential PI3K/mTOR signaling pathway activation has been observed in most breast cancers. The cell growth and tumor development in such cases involves phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) complex intracellular pathway. Hypothesis: Through preclinical and clinical trials, it has been observed that there are a number of other inhibitors of PI3K/Akt/mTOR pathway, which either alone or in combination with cytotoxic agents can be used for endocrine therapies. Conclusions: Structure and regulation/deregulation of mTOR provides a greater insight into the action mechanism. Also through this review, one could easily scan first and second generation inhibitors for PI3K/Akt/mTOR pathway besides targeted therapies for breast cancer and the precise role of mTOR.

1. Send Orders for Reprints to reprints@benthamscience.ae
Current Pharmaceutical Design, 2017, 23, 1-6 1
REVIEW ARTICLE
1381-6128/17 $58.00+.00 © 2017 Bentham Science Publishers
PI3K/Akt/mTOR Intracellular Pathway and Breast Cancer: Factors, Mechanism and
Regulation
Var Ruchi Sharma1
, Girish Kumar Gupta2
, A.K. Sharma3
, Navneet Batra4
, Daljit K. Sharma5
, Amit Joshi6
and
Anil K. Sharma1,
*
1
Department of Biotechnology, Maharishi Markandeshwar University, Mullana-Ambala (Haryana) India-133207; 2
Department of
Pharmaceutical Chemistry, M.M.College of Pharmacy, Maharishi Markandeshwar University, Mullana-Ambala (Haryana) India-
133207; 3
Department of Physics, Maharishi Markandeshwar University, Mullana-Ambala (Haryana) India-133207; 4
Department of
Biotechnology, GGDSD College, Sec 32 Chandigarh India-160032; 5
Deparment of Science, Gurukul Global School, Chandigarh.
India; 6
Department of Biotechnology & Bioinformatics, SGGS College, Sector 26 Chandigarh. India-160019
A R T I C L E H I S T O R Y
Received: August 2, 2016
Accepted: October 28, 2016
DOI: 10.2174/1381612823666161116
125218
Abstract: Background: The most recurrent and considered second most frequent cause of cancer-related deaths
worldwide in women is the breast cancer. The key to diagnosis is early prediction and a curable stage but still
treatment remains a great clinical challenge.
Origin of the Problem: A number of studies have been carried out for the treatment of breast cancer which in-
cludes the targeted therapies and increased survival rates in women. Essential PI3K/mTOR signaling pathway
activation has been observed in most breast cancers. The cell growth and tumor development in such cases in-
volves phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) complex intracellular
pathway.
Hypothesis: Through preclinical and clinical trials, it has been observed that there are a number of other inhibi-
tors of PI3K/Akt/mTOR pathway, which either alone or in combination with cytotoxic agents can be used for
endocrine therapies.
Conclusions: Structure and regulation/deregulation of mTOR provides a greater insight into the action mecha-
nism. Also through this review, one could easily scan first and second generation inhibitors for PI3K/Akt/mTOR
pathway besides targeted therapies for breast cancer and the precise role of mTOR.
Keywords: PI3K/Akt/mTOR, breast cancer, cell proliferation, intracellular, cytotoxic, therapy.
INTRODUCTION
The PI3K/Akt/mTOR pathway has been known to be frequently
modified in breast cancer as well as in other types of cancers and
therefore has been identified as an important target in breast cancer
research. First-generation inhibitors of mammalian target of ra-
pamycin (mTOR) have been currently approved for the treatment
of breast, pancreatic, renal, and some brain cancers. Moreover some
of the second-generation mTOR inhibitors and novel agents target-
ing PI3K or Akt are in early clinical trials [1].
The mTOR is alternatively known as FK506-binding 12-
rapamycin-associated protein 1 (FRAP1). mTOR is basically a
serine/threonine protein kinase which controls growth,
proliferation, survival, motility, protein synthesis, transcription and
autophagy. This pathway is considered as a central regulator in
various types of tumorigenesis and metastasis including obesity,
type-2 diabetes and neurodegeneration. The mTOR gene is located
on human chromosome 1 at location 1p36.2 and is identified as a
289 kDa serine/threonine kinase consisting of 2549 amino acids in
mammalian cells [2].
STRUCTURE-FUNCTION RELATIONSHIP OF MTOR
There are two different complexes of mTOR which are struc-
turally and functionally different: mTORC1 and
*Address correspondence to this author at the Department of Biotechnology,
M.M. University, Mullana-Ambala -133207; Tel: +91-8059777758;
Fax: +91-01731274375; E-mail: anibiotech18@gmail.com
mTORC2.https://en.wikipedia.org/wiki/Mechanistic_target_of_rapa
mycin - cite_note-Wull-15 Both types of complexes are present in
different subcellular compartments and thereby influencing their
function and activation [3].
MTORC1
mTORC1 consists of five components: mTOR, mammalian
lethal Sec13 protein 8 (mLST8), Raptor, proline rich AKT substrate
40 kDa (PRAS40) and Deptor. mTOR is the catalytic subunit of the
complex while Raptor is the regulatory-associated protein of
mTOR. On the other hand, Deptor is a DEP-domain-containing
mTOR-interacting protein. The function of Raptor is to enroll sub-
strates for mTOR and regulate formation of the complex. The dele-
tion of mLST8 does not affect mTORC1 activity in vivo. PRAS40
and Deptor are distinct negative regulators of mTORC1. PRAS40
and Deptor are engaged in the mTORC1 complex and promote the
inhibition of the complex when the activity of the mTORC1 is re-
duced. PRAS40 acts as a direct inhibitor of substrate binding by
regulating mTORC1 kinase activity [4]. When activated, mTORC1
phosphorylates PRAS40 and Deptor, revealing a decreased physical
interaction with mTORC1 and further stimulating mTORC1 signal-
ing. mTORC1 controls protein and lipid biosynthesis, autophagy,
mitochondrial metabolism, biogenesis and acts as a nutrient/energy/
redox sensor. mTORC1 activity is controlled by various growth
factors, serum, insulin, amino acids and oxidative stress etc. (Fig.
1A).

2. 2 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Sharma et al.
MTORC2
mTORC2 consists of six different proteins: mTOR, rapamycin-
insensitive companion of mTOR (Rictor), mSIN1; Protor-1;
mLST8; and Deptor. mTOR, mLST8 and Deptor are shared be-
tween mTORC1 and mTORC2. Rictor and mSIN1 stabilize each
other. Rictor is also known to interact with Protor-1. Like in
mTORC1, Deptor negatively regulates mTORC2 activity [5].
mLST8 is critical for mTORC2 function, as knockout of this pro-
tein strictly reduces the stability and the activity of this complex6
.
mTORC2 is also known to be an important regulator of the cy-
toskeleton through its stimulation of paxillin, Rac1, F-actin stress
fibers, RhoA, and Cdc42. At the serine residue S473, mTORC2
phosphorylates the serine/threonine protein kinase Akt/PKB and
thereby affecting metabolism and survival (Fig. 1B).
The domain structure of mTOR comprises of six functional
domains [7-9] (1) HEAT domain (Huntington elongation factor 3
which is a subunit of protein phosphatase 2A and TOR1) which is
known to mediate protein-protein interactions; (2) FAT (FRAP-
ATM-TRAPP) domain; (3) FRB (FKBP12-rapamycin binding)
domain which exhibits inhibitory action of rapamycin on Raptor-
bound mTOR; (4) PIKK (PI3-kinase-related kinase) domain; (5)
RD (Repressor domain); and (6) the carboxy-terminal FATC do-
main [10] (Fig. 1C).
The N terminus of mTOR consists of 20 tandem HEAT repeats
while the C-terminal half of mTOR contains the kinase domain
(catalytic domain). The FRB and FAT domain is present upstream
of the catalytic domain. The first 1350 residues of mTOR consist
exclusively of HEAT repeats followed by the 650-residue FAT
domain that comprises numerous TPRs (tetratricopeptide re-
peats).[11] Both types of repeats form extended superhelical do-
mains essential for protein-protein interactions [12]. The FAT do-
main consists of 28 alpha helices arranged in repeats which forms a
“C” shaped solenoid around the kinase domain. The FRB domain
consists of 100 residues required for binding to RAPTOR and RIC-
TOR and present in between FAT and kinase domain. The kinase
domain consists of 550 residues and has two lobes: - N-terminal
and C-terminal lobe and a cleft in between these lobes bind to ATP.
The C-lobe forms the binding site for mLST8. The FATC domain
consists of 35 residues present at the C-terminus [13]. The deletion
of repressor domain causes the activation of mTOR and is located
in between the kinase and FATC domain [14].
PATHWAY PI3K/AKT/MTOR
PI3K/AKT/mTOR pathway is a cell cycle regulation pathway
that is a key regulator of cell metabolism, growth, proliferation and
cell survival. The activation of the pathway starts with different
cellular processes like angiogenesis; formation of tumor etc. [15-
19]. PI3K/AKT complex activates mTORC1 and is inhibited by the
complex TSC1/TSC2 while mTORC2 is known to be activated by
growth factors. mTORC1 regulates ribosomal formation and pro-
tein synthesis through the phosphorylation followed by inactivation
of the repressor of mRNA translation 4EBP1 and phosphorylation
and activation of S6K.
Moreover mTORC1 also regulates a number of proteins includ-
ing CLIP-170 (cytoplasm linker protein-170) [20], HIF-1 α (hy-
poxia-inducible factor 1α) [21], eEF2 (eukaryotic elongation factor
2) kinase [22], lipin, glycogen synthase, ODC (ornithine decarboxy-
lase), PKCδ and PKCɛ, PP2A (protein phosphatase 2A), p21Cip1
and p27Kip1 cyclin-dependent kinase inhibitors, retinoblastoma
protein, and activator of transcription-3. mTORC2 phosphorylates
AKT, PKC-α and paxillin (focal adhesion-associated adaptor pro-
tein), and also regulates the activity of the small GTPases Rac and
Rho.
mTOR has been known to be a vital regulator of cell growth
and proliferation. The pathway regulation in mTOR is facilitated
either by various growth factors or by ATP, amino acids and oxy-
gen levels. The mTORC1 signaling is known to be stimulated by
phosphorylated AKT. The Second messenger PtdIns (3,4,5) P3 is
known to be produced by Class I PI3K. Upon generation, this sec-
ond messenger binds to the pleckstrin-homology (PH) domain of
AKT and PDK1. PtdIns (3,4,5) P3 to the PH domain of AKT brings
the kinase to the cell membrane formed by its activation by phos-
phorylation of PDK1 at Thr308 position and by phosphorylation of
mTORC2 at Ser473 position. PTEN negatively controls AKT acti-
Fig. (1). Domain Structural Organization of mTOR.

3. PI3K/Akt/mTOR Intracellular Pathway and Breast Cancer Current Pharmaceutical Design, 2017, Vol. 23, No. 00 3
vation, as it transform PtdIns (3,4,5) P3 to PtdIns(4,5) P2, resulting
in decreased recruitment of AKT to cell membrane. A number of
downstream substrates, as well as FOXO transcription factors,
GSK3 and TSC2 activate AKT. The complex formation of complex
TSC1/TSC2 is stopped by phosphorylation of TSC2, which moves
the small GTPase Rheb into the GTP-bound active state [23] which
leads to the activation of mTORC1 at Ser2448 [24]. Upon phos-
phorylation and inhibition of PRAS40 by AKT, regulates mTORC1
negatively by turning around its activation by Rheb [25]. Both
S6K1 and 4EBP1 gets phosphorylated by mTORC1 which is acti-
vated, by interrelating raptor and a TOR signaling (TOS) motif in
S6K and 4EBP. S6K1 is further triggered by TOR-insensitive sig-
naling pathways such as PDK1, MAPK and SAPK (stress-activated
protein kinase). Despite of this, the phosphorylation of S6K1 is
essential for its activation through mTORC1 and the phosphoryla-
tion sites of S6K1 are blocked by mTOR inhibitors. S6K1 is phos-
phorylated by mTORC1 (activated), which further phosphorylates
40S ribosomal protein S6 further increasing the translation of
mRNAs with a 5′-terminal oligo-poly-pyrimidine. The targets of
S6K1 include elongation factors, ribosomal proteins, and insulin
growth factor 2 [26].
4EBP1 binds to eIF4E (eukaryotic translation initiation factor
4E) and inactivates it and therefore inhibits the initiation of protein
translation [27]. For dissociation of eIF4E from 4EBP1, mTORC1
phosphorylates 4EBP1 at multiple sites and therefore alleviate the
inhibition of 4EBP1 on eIF4E-dependent translation beginning
(Fig. 2).
UPSTREAM REGULATION OF THE MTOR PATHWAY
mTORC1 signaling is activated by class I P13K and AKT in the
presence of growth factors, hormones and nutrients. The stimula-
tion of S6K1 and 4EBP1 phosphorylation by amino acids occurs in
the presence of mTORC1. Due to withdrawal of amino-acids,
dephosphorylation of S6K1 and 4EBP1 occurs rapidly, however the
addition of amino acids relieves this action in a rapamycin-sensitive
manner [28]. The energy level status of cells also affects the mTOR
activity. When the energy level is low, the activity of mTOR1 is
suppressed by the phosphorylation of TSC2 by AMPK (AMP-
activated protein kinase) [29]. Further LKB1 (Liver kinase B1)
activates AMPK [30]. Rheb-GTP is required for amino acid medi-
ated regulation of mTORC1 whereas TSC1/TSC2 complex is not
essential. Activity of mTORC1 can be affected by amino acids via
hVps34 (human vacuolar protein sorting-34) and class III PI3K
[31]. The activation of mTORC1 signaling is also triggered by
RAS/MAPK signaling. RAS proteins function as a GDP/GTP-
regulated switch. RAS is GDP-bound in normal inactive cells. The
Fig. (2). mTOR signaling pathway.

4. 4 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Sharma et al.
activated form of GTP-bound of RAS binds and activates RAF
kinase in the presence of growth factors, hormones or cytokines.
When activated, RAF phosphorylates and activates MEK that fur-
ther triggers ERK/RSK pathway and regulates gene expression
[32]. cytoskeleton and metabolic remodeling. The phosphorylation
of TSC2 is inhibited by ERK and RSK that enhances TSC1/TSC2
dissociation and results in mTORC1 activation. Inhibitor of nuclear
factor κB (NFκB) kinase β) (IKKβ) phosphorylates TSC1 and in-
hibits the complex formation of TSC1/TSC2 and thus activates
mTORC1. TNFα (tumor necrosis factor α) also activates mTORC1
activity by activating AKT. In the presence of growth factors,
mTORC2 is known to phosphorylate AKT.
PI3K/AKT/MTOR PATHWAY DEREGULATION
PI3K is a major signaling downstream regulator of HER2 (hu-
man epidermal growth factor receptor 2) and other growth factors.
The expression of PI3K/AKT/mTOR signaling is frequently altered
in breast cancer through a variety of mechanisms like mutations
and/or amplification in PI3K of AKT, increased expression or es-
tablishment of growth factor receptors, such as IGFR (insulin-like
growth factor receptor) and HER-2 [33]. PI3K is negatively regu-
lated by PTEN and is deregulated through mutation, methylation,
protein instability, loss of heterozygosity, anomalous expression of
regulatory microRNA. S6K1, 4EBP1 and eIF4E are mTOR down-
stream effectors and are linked in cellular transformation, and their
increased expression has been associated with poor cancer progno-
sis [34]. Some factors like loss of PTEN function, deregulation of
mTOR pathway may happen due to amplification/mutation of
PI3K, increased expression of S6K, AKT, eIF4E and 4EBP1. Loss
of PTEN function is caused by promoter methylation and regulation
at RNA or protein level. In 70% cases, breast cancer occurs due to
mutations in genes that constitute phosphatidylinositol 3-kinase
(PI3K) pathway. The frequency of mutations in different breast
cancer types has been rated as follows [35]:
• Over-expression of HER2: 10% ER+ and 100% HER+
• Loss of PTEN function: 29-44% ER+, 22% HER+ and 67%
Triple Negative
• Hyper-activation of AKT: 2-3% ER+
• Over-expression of PDK1: 22% ER+, 22% HER+ and 38%
Triple Negative
• Amplification of IGFR: 41-48% ER+, 18-64% HER+ and 42%
Triple Negative
• In order to get insight into the therapeutic potential of various
molecules, Table 1 mentions about some of the key targeted
therapies being employed against breast cancer.
mTOR IN OTHER CANCERS
Mammalian target of rapamycin (mTOR), a protein kinase,
which is encoded by mTOR gene in humans is known to have a role
Table 1. Targeted therapies for breast cancer.
Therapy Target Information
Rapamycin and its
rapalogs
FKBP-12 The rapamycin-FKBP-12 complex inhibits mTOR preventing further phosphorylation of P70S6K, 4E-BP1
and other proteins occupied in transcription and translation and cell cycle control [36].
INK-128 AKT, P70S6K,
S6RP, and 4EBP1
INK-128 is a potential and unique ATP competitor of both mTORC1 and mTORC2, is recently in clinical
development for the treatment of breast cancer. INK-128 did not cause the mTORC2 activation of AKT
and blocked mTORC1, mTORC2. The treatment with INK-128 inhibits the phosphorylation of
AKT(S473), P70S6K, S6RP, and 4EBP1 [37].
GDC-0980 PI3K and mTOR GDC-0980 is an effective and potential dual PI3K/mTOR inhibitor and inhibits signal transduction down-
stream of both PI3K and mTOR [38].
WAY-600 eEF2, AKT WAY-600 is an ATP-competitive and potential inhibitor of mTOR. WAY-600 stimulates phosphorylation
and inactivation of the translation elongation factor eEF2. WAY-600 also blocks mTORC2-dependent
phosphorylation of AKT [39].
MLN0128 mTORC1,
mTORC2, AKT
MLN0128 is an investigational drug which inhibits both the complexes of mTOR (mTORC 1 and
mTORC2). MLN0128/TSA combination reduces phosphorylation of AKT at S473 and inhibits AKT acti-
vation [40].
Piceatannol PI3K, AKT Piceatannol attenuated PI3K and phosphorylation of mammalian target of rapamycin (mTOR) and AKT.
Piceatannol also inhibits MMP-9 involved in PI3K/AKT and NF-κB pathways. Moreover, piceatannol
distinctly inhibited the activity of matrix metalloproteinase-9 (MMP-9) and expression at both protein and
mRNA levels [41].
RY10-4 AKT, HIF-1α RY10-4 is a novel anti-tumor compound exhibiting anti-angiogenesis activity by inhibition of phosphory-
lation of AKT and mTOR by down-regulation of the HIF-1α [42].
Gefitinib EGFR Gefitinib is an epidermal growth factor receptor's (EGFR) inhibitor. Gefitinib associated to adenosine
triphosphate (ATP)-binding site of the enzyme resulting in inhibition of EGFR tyrosine kinase which fur-
ther inhibits anti-apoptotic Ras signal transduction cascade [43].
Miconazole HIF-1α, eIF2α Miconazole suppressed hypoxia inducible factor-1α (HIF-1α) protein expression through post-
transcriptional regulation. The suppressive effect of HIF-1α protein synthesis was affected due to inhibition
of mTOR. Miconazole significantly reduced the expression of its target VEGF and the transcriptional
activity of the HIF-1 complex. Moreover, miconazole inhibits global protein synthesis by initiating phos-
phorylation of the translation initiation factor 2α (eIF2α) [44].

5. PI3K/Akt/mTOR Intracellular Pathway and Breast Cancer Current Pharmaceutical Design, 2017, Vol. 23, No. 00 5
in cell growth regulation, proliferation, cell survival, motility, pro-
tein synthesis and transcription.
miRNA-21 through PI3K/AKT/mTOR pathway suppresses
PTEN and also acts on ovarian cancer and it is activated by AKT in
hypoxic conditions. In 80% of ovarian carcinoma, fatty acid syn-
thase (FASN) is known to be over expressed, while the individual
members of the PI3K/AKT/mTOR pathway are not affected.
PI3K/AKT/mTOR may be activated by the loss of sMEK. It was
found that sMEK1 was down regulated in cervical tumor and ovar-
ian tissue [45]. Cell proliferation can be suppressed due to the re-
expression of sMEK1 in the OVCAR-3 cells by adding cell cycle
arrest at G1/G0 phase with an increase in CDK inhibitor p16, and
p27 [45]. Moreover, PI3K and AKT de-phosphorylation can be
induced while expression of the mTOR/p70S6K proteins may be
reduced by sMEK1.
Insulin-like growth factor binding protein-3 mediates interleu-
kin-24-induced apoptosis through inhibition of the mTOR pathway
in prostate cancer [46], IGFBP-3 significantly enhanced interleu-
kin-24 (IL-24)-induced cell death in prostate cancer (PC) cell lines
in vitro. Both the addition of IGFBP-3 to cell medium and the en-
forced expression of IGFBP-3 in the PC cells inhibited activation of
mammalian target of rapamycin (mTOR). Down regulation
of mTOR/S6K reduced Mcl-1 protein expression and consequently
enhanced sensitization to IL-24 treatment. The over expression of
Mcl-1 decreased the level of cleaved poly (ADP-ribose) polymerase
(PARP) induced by IL-24 and IGFBP-3 [47].
Down-Regulated Neurensin-2 (NRSN2) was found to encour-
age cell Survival and Proliferation through PI3K/Akt/mTOR Path-
way in Hepatocellular Carcinoma [48]. NRSN2 was more com-
monly down-regulated in HCC tissues compared with adjacent
tissues. NRSN2 was also reported to inhibit cancer cell proliferation
and promote cancer cell senescence and apoptosis. Overall, NRSN2
plays a significant role in HCC cell proliferation and apoptosis by
regulating PI3K/AKT signaling and p53/p21 pathway [49].
CONCLUSION
This review article provides the detailed information of various
components and their role in the regulation of PI3K/AKT/mTOR
pathway. The deregulation of PI3K/AKT/mTOR pathway seems to
be responsible for the occurrence of breast cancer through genetic
alterations that can result in unrestricted cellular proliferation and
increased cell survival. This pathway is deregulated through muta-
tions in PI3K & AKT and due to over expression of some growth
factors like HER2 and IFGR. There are multiple inhibitors of
PI3K/AKT/mTOR pathway which as single agent or in combina-
tion of other therapies can be used to treat even many other cancers.
The first generation mTOR inhibitors (like rapamycin and its rapa-
logs) inhibit only mTOR1 activity while second-generation mTOR
inhibitors (like MLN0128, INK-128) inhibit the function of both
mTOR1 and mTOR2 activity. Deeper insight into the said pathway
can lead to further exploration towards more developed and updated
cancer therapies.
SCOPE AND SIGNIFICANCE
The activation of PI3K/AKT/mTOR signaling pathway plays a
significant role in controlling cell growth, cell proliferation, gene
transcription and translation of mRNA. There exists a close rela-
tionship between mTOR activity and development of tumor.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
Declared none.
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