Potential Therapeutic Targets for TNBC Therapy: History
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Subjects: Pharmacology & Pharmacy
Contributor:
AISWARYA CHAUDHURI
,
Ashish Agrawal
,
Dulla Naveen Kumar
,
,
Pradeep Kumar
,
Pradeep Kumar Bolla
,
Dinesh Kumar
TNBC exhibits high heterogeneity, which is the major limitation of chemotherapy. Also, TNBC is regarded as an aggressive type of cancer that grows faster and metastasizes to the brain and visceral organs, providing a much shorter average survival time of about 12 months to patients suffering from advanced TNBC. Therefore, the recognition of definitive targets, for providing efficient treatment against TNBC, becomes a noteworthy task.
  • chemotherapy
  • nanoparticles
  • targeted therapy
  • triple-negative breast cancer (TNBC)

1. Notch Signaling Pathways

The Notch signaling pathway is considered an exceptionally preserved targeted pathway that involves juxtracrine (cell-to-cell) communication, thus regulating several critical cellular processes [[1]]. Notch signaling is known for regulating self-renewal as well as differentiation processes, required for normal development of the mammary gland [[2],[3]]. It was observed that the signaling pathway is triggered when the Notch ligand interacts with the Notch receptor, situated on the adjoining cell. Up till now, four Notch receptors and five Notch ligands have been identified. The five Notch ligands identified are Delta-like (DII)-1, 3, and 4, and Jagged (JAG)-1, and 2. Structurally, it was observed that all the Notch ligands are transmembrane proteins, having an extracellular DSL domain and multiple EGF-like repeats. The extracellular DSL domain is responsible for mediating the binding process between the Notch receptor and Notch ligands. In addition to this, the JAG ligand consists of an extra domain enriched with cysteine, which is absent in the DII ligand [[4]]. It was observed that a Notch ligand-receptor complex was formed when the Notch ligand binds with the Notch receptor. The binding procedure is facilitated by two proteolytic enzymes, i.e., ADAM (disintegrin metalloprotease) and TACE (TNF-α converting enzymes), which further aids in releasing the ectodomain of the Notch receptor [[5],[6]]. The proteolytic activity then converts the Notch ligand-receptor complex into NEXT (Notch extracellular truncation). Finally, the NEXT is broken down via γ-secretase, and the Notch intracellular domain (NICD) get discharged, which then translocates from the cytoplasm to the nucleus [[7]], where it binds with the transcriptional activator, namely CSL complex (CBF1, RBPJK/Su(H)/LAG1, and Mastermind (MAML1-3, and MED3)) [[8],[9]]. The binding then orchestrates CSL-complex activation, leading to transcription of downstream targets, which includes genes like ER, Hes, Hey, and VEGFR3 (vascular endothelial growth factor receptor 3), transcriptional factors like NF-κB2 and c-Myc, cell cycle regulators (cyclin D1 and p21), growth factor receptors, and angiogenesis and apoptosis modulators [[1],[10]]. It was observed that dysregulation of the Notch signaling pathway often leads to aberrant self-renewal and differentiation of stem cells, which results in carcinogenesis [[11],[12]].
In a study by Speiser et al., 2012, it was found that the progression of TNBC was associated with increased expression of Notch 1 and Notch 4 receptors [[13]]. The abnormal activation of NOTCH receptors results in aberrant controlling of the transcription of several oncogenes as well as tumor suppressor genes [[14]], which include CYCLIN D1, c-MYC, PTEN, and the BCL-2 pro-survival proteins [[15],[16],[17]]. Loss or reduced expression of NICD, NUMB (a negative regulator of EMT) also leads to TNBCs in association with poor clinical outcomes [[18],[19]]. In 1987, Gallahan et al. inserted a mutagenic mouse mammary tumor virus (MMTV), which then generated truncated and active Notch1 and 4 receptors, resulting in the formation of breast cancer in mice [20]. On a similar trait, in 2013, Reipas and his associates revealed that p90 ribosomal S6 kinase, an oncogenic transcription factor is required for the growth of TNBC, which was found to be an activator of the Notch4 signaling pathway [[21]]. Thus, there exists strong evidence that indicates the involvement of the NOTCH signaling pathway, especially NOTCH1/NOTCH4 into the etiology of TNBC. Hence, targeting the Notch signaling pathway should provide a promising treatment platform against TNBC.

2. Hedgehog (Hh) Signaling Pathway

Hh signaling is also considered a preserved pathway, just like notch pathways. Hh signaling acts as a key signaling cascade in the proper development of the embryonic mammary gland as well as ductal morphogenesis. Hh signaling is also known to take part in EMT [[22]]. Hh signaling pathway is comprised of three ligands, namely Sonic Hedgehog (Shh), Desert Hedgehog (DHh), and Indian Hedgehog (IHh), where Sonic Hedgehog was regarded as the most targeted, one transmembrane receptor, PTCH, and one co-receptor, SMO. It was observed that the co-receptor SMO is required for the functioning of the Hh signaling pathway, but it has been inhibited by PTCH. So, the binding of the Hh ligand with the PTCH receptor led to its inactivation, which indirectly activates the SMO co-receptor. The activated SMO leads to the formation of a multiprotein complex, GLI complex, considered a hallmark in Hh pathway activation. Further, the functioning of the GLI complex is mediated by transcription factors GLI1, GLI2 (activator of the complex), and GLI3 (inhibitor of the complex). The activated GLI complex gets translocated in the nucleus, where the GLI1 and GLI2 transcription factor gets upregulated and engages itself in the transcription process, causing metastasis, angiogenesis, and apoptosis, resulting in the development of TNBC [[23]]. The transcription process also enhances the expression of proteins responsible for metastasis (SNAIL), and angiogenesis (angiopoietin-1, and 2) [[24], [25]]. Moreover, SMO directly activates MYCN, which elevates the expression of transcription factors, FOXM 1 and cyclin D, leading to the proliferation of TNBC cells [[26]]. Furthermore, it was observed that the other transcription factors, namely NF-kB, FOXC1, and Hypoxia-induced factor (HIF)-1α are also involved in the deregulation of Hh signaling, along with TGF-β, RAS/MAPK (mitogen-activated protein kinases) signaling pathways, and the extracellular matrix protein osteopontin (OPN), thus, overall contributing to enhanced growth and invasion of TNBC [[27]]. It was reported by Mukherjee et al., 2006, that 70% of ductal carcinomas and 30% of metastatic breast cancer showed an overexpression of SMO receptors [[28]].

3. Wnt/β-Catenin Pathway

The Wnt signaling pathway serves a vital role in the patterning of embryonic tissue, migration of cells as well as its adhesion, maintenance of stem cells, and mediating epithelial-mesenchymal interactions [[10]]. This signaling pathway activates when Wnt proteins bind with LRP5/6 protein (LDL receptor-related protein5/6), and Frizzled protein (FZD; seven-pass transmembrane receptor protein) [[29]]. In absence of Wnt proteins/ligands, β-catenin is concealed within a complex comprising of axin, adenomatous polyposis coli (APC) tumor suppressor, glycogen synthase kinase-3β (GSK3β), and casein kinase 1 (CK1), which later triggers phosphorylation of β-catenin via CK1 and GSK3β and results in ubiquitination. This ubiquitination then compels the 26S proteasome to degrade β-catenin [[30]]. However, when Wnt proteins interact with LRP5/6 and FZD, they form a complex called the Wnt-LRP5/6-FZD complex, which inhibits GSK3β and leads to the cytosolic β-catenin stabilization. The free β-catenin then translocates from the cytoplasm to the nucleus, where it associates with T-cell factor (TCF)/lymphoid enhancing factor (LEF) to activate the expression of various downstream targeted genes that are responsible for regulating cell growth, proliferation, and apoptosis, thus mediating initiation as well as the progression of TNBC [[31]]. In a study, the up-regulated expression of FZD and LRP5/6 in TNBC cells was also observed. Also, TNBC cells exhibit a transcriptional knockdown of FZD/LRP6 that establishes its restraining activity in vivo. It was further generalized that the association of the Wnt/β-catenin pathway with the progression of TNBC is related either with a gain of nuclear β-catenin or loss of membranous β-catenin [[32]].

4. TGF-β Signaling Pathway

The TGF-β signaling pathway is a pathway involved in the growth of cells, their differentiation, homeostasis, as well as apoptosis. TGF-β cytokines are comprised of many members, out of which TGF-β1, encoded via TGF-β1 gene [[33],[34]] has been announced to play an essential part in breast cancer stem cells (BCSC). It was observed that the TGF-β receptor 1 (TGFBR1) is overexpressed in BCSC [[35]]. On further study, it was found that TGF-β1 induces EMT in mammary cells, which results in tumor formation [[36]]. This was further evidenced by a study performed by Sendurai et al., 2008, which exhibited that the mammary stem cells indicated increased expression of TGF-β1, thereby increasing their ability of mammospheres formation along with EMT gene expression like N- and E- cadherin, Slug, and Snail, associated with TNBC progression. On a similar note, Michael et al., 2011, reported that the CSCs (cancer stem cells) formed by TGF-β/TNFα induced EMT, showed enhanced self-renewing capacity along with increased tumorigenicity and chemotherapeutics resistance [[37]]. Also, the TGF-β1 pathway was found to generate SMAD2/3 and SMAD4 expression, causing activity like the synthesis of protein, growth proliferation, metastasis, and angiogenesis [[1]]. Thus, it could be inferred that TGF-β signaling plays a crucial character in the activation of EMT and procuring stemness, hence this pathway has been suggested as a novel therapeutic approach against TNBCs.

5. PI3K/AKT/mTOR Signaling Pathway

PI3Ks are considered an important molecule of the PI3K/AKT/mTOR signaling cascade that lead to the growth of tumor cells. PI3Ks are heterodimers composed of p85 (regulatory subunit), and p110 (catalytic subunit). There are four PI3Ks isoforms currently known, namely α, β, ϒ, and δ [[38]]. PI3K/AKT/mTOR signaling pathway gets activated when stimulated by tyrosine kinases receptor, which further causes activation of PI3K, followed by AKT and mTORC1 phosphorylation [[39]]. The mTOR is a kinase protein composed of serine/threonine, responsible for controlling cellular proliferation, cellular growth, motility, and survival, as well as protein synthesis and transcription [[40],[41]]. mTOR is comprised of two complexes, namely mTORC1 and mTORC2. It was found that both mTORC1 and mTORC2 induce S-phase kinase association protein, which leads to the synthesis of protein, growth, and proliferation of cells along with metastasis and angiogenesis. Hence, the progression of TNBC is found to be associated with the deregulation of the mTOR pathway [[1]]. It was further observed from the studies that in TNBC, the actuation of the PI3K/AKT/mTOR signaling pathway was also mediated via overexpression of EGFR (upstream regulators), and proline-rich inositol polyphosphatase (downstream regulator), mutation of the PIK3Cα, and loss of expression of PTEN [[42],[43], [44]]. Further, it was observed that the inactivation of p53 protein unleashes various tumorigenic pathways like FGFR (fibroblast growth factor receptor), cMET, and RAF (rapidly accelerated fibrosarcoma) kinases, which then activates the PI3K/AKT/mTOR signaling pathway [[45]]. However, TNBC progression was found to be rare when termed with the mutation of other downstream regulators of PI3K/AKT/mTOR signaling pathway (AkT, and mTOR) as well as cognate pathway (RAS, and MAPK) [[46]]. Thus, it could be inferred that the PI3K/AKT/mTOR signaling pathway can be used as a potential target of TNBCs.

6. EGFR

EGFR is a transmembrane tyrosine kinase receptor, belonging to the family of HER/erythroblastosis virus oncogene B (ErbB) [[47],[48]]. EGFR is responsible for regulating cell proliferation, cell differentiation, cellular invasion along with angiogenesis and apoptosis. Also, EGFR regulates the expression of Akt (PKB) and MAPK, responsible for inducing drug resistance [[49],[50]]. Initially, EGFR was regarded as a target of lung cancer only, however, through recent studies it was revealed that EGFR also plays a role in the progression of TNBC [[50]]. It was revealed in a study that unlike the mutation of EGFR in the case of lung cancer, the progression of TNBC is related to an increased number of EGFR genes, and not the mutation of EGFR [[51]]. EGFR-overexpressing TNBCs were regarded as basal-like high-grade carcinomas. On the binding of BRCA1 to the miR-146a promoter, there occurs an increase in miR-146a transcriptional levels, which allows the binding of miR-146a to the 3’UTR of EGFR for promoting the degradation of its mRNA. As the TNBC is related to the EGFR gene number, it could be stated that the deficiency of BRCA1 and miR-146a prevents the degradation of mRNA, which in turn increases the number of gene expressions of EGFR and p-EGFR (Y1068) [[52],[53]]. It was found that approximately 36% to 89% of TNBC showed an overexpression of EGFR. Further, it was observed that the survival of disease-free patients of TNBC patients is negatively associated with the overexpression of the EGFR gene [[51],[53],[54]]. Hence, it is reflected that EGFR can serve as a potential target for TNBC therapy.

7. IGF1R

In a clinical study, it was found that 50–75% of TNBCs showed enhanced expression of the IGF1R. IGF1R causes growth, invasion, as well as metastasis in patients suffering from TNBC. It has been reported that IGF1R increases the metastasis in cancer cells by inducing anchorage-independent growth, which became evident from a pre-clinical trial that showed an over-expression of IGF1R in the tumor initiation site as well as in the site where metastasis took place. Further, it was observed that IGF1R also inhibits the apoptosis caused due to the administration of the chemotherapeutic drug, hence suggesting an incidence of chemo-resistance [[55]].

8. PARP1

PARP1 belongs to the class of DNA repair enzymes, and plays a vital character in managing genomic stability, DNA repairing, regulating the progression of the cell cycle, and apoptosis [[56]]. PARP1 responds to single-stranded DNA damage via various repairing mechanisms like base excision repair mechanism, nucleotide excision repair mechanism, or mismatch repair mechanism and hence maintains the genomic integrity [[57]]. Hence, it could be stated that PARP1 inhibition causes loss of DNA repair functioning, inducing apoptosis [[57]].
On a similar note, it was observed that in the absence of the PARP1 enzyme, an aggregation of single-strand breaks (ssDNA) occurs, resulting in the generation of double-strand breaks (dsDNA), which were then repaired by homologous recombination (HR). HR is an error-free repairing process involving BRAC1 and BRAC2 proteins. So, the presence of PARP1 inhibits the functioning of HR, causing mutations in BRAC proteins [[58]], and from various studies, it was found that ≈70% of mutated BRCA1 and ≈16–23% of mutated BRCA2 breast cancers are regarded as TNBCs [[59]]. Therefore, inhibition of the PARP1 enzyme can also be used as a target in TNBC therapy.

9. Src Kinases

Src is a tyrosine kinase protein of the non-receptor type that belongs to the Src family kinases (SFKs). Src gets activated by two means, either via cytoplasmic proteins like focal adhesion kinase (FAK), Crk-associated substrate (CAS), playing a distinct role in integrin signaling, or via activation of ligand belonging to cell-surface receptors like EGFR, FGFR, VEGFR, etc. It was observed that SRCs regulate various signal transduction pathways associated with cell adhesion, cell migration, invasion, and angiogenesis [[60]]. In a study, it was found that TNBC is associated with overexpression of c-SRC kinases, also known as proto-oncogene tyrosine-protein kinase Src. The overexpression of c-Src in TNBC is responsible for tumorigenic proliferation, migration, and invasion [[61], [62]111,112]. Also, c-Src overexpression facilitates bone metastases in the case of metastatic TNBC. It was found that the increased activity of Src kinase is either due to its increased transcription or due to its deregulation caused by the overexpression of the upstream growth factor receptors including EGFR, PDGFR, FGFR, VEGFR, integrin, FAK, etc. [[60]].

10. Immune-System Targeting

Immune checkpoint inhibitors like anti-PD-1, anti-PD-L1, and anti-CTLA-4 demonstrate a novel type of immunotherapy for the treatment of cancer. It was found that in cancer progression, the immune response gets compromised. Research evidence revealed that T-lymphocytes are responsible for activating the distinct immune responses against an emerging antigen. Further, it was observed that lymphocyte surface receptors get stimulated when interacting with an antigen-presenting cell (APC) [[63]]. Cell activation needs definite identification of the presented antigen, as well as a specific signal from co-stimulators that are mobilized during the generation of the immune synapse. Such cell effector functions are inhibited by signals produced by negative cell receptors. The stated mechanism is anticipated to prevent the undesirable effects of overstimulation, causing an autoreactive response or stimulation of carcinogenesis once the defensive role of the lymphocyte antigen is swept. PD-1 (CD279) belongs to such type of negative receptor. Similar to PD-1, CTLA-4 is also a negative receptor available on APC, which on binding with CD80-B7-1, and CD86-B7-2 ligands activates an inhibitory reaction, which suppresses the immune responses, blocks the responses of T-lymphocytes, decreases the T-lymphocyte proliferation, and limits the secretion of cytokine. All of these contribute to an immune deficiency in cancer patients [[64]].
Hence, it was suggested that immunotherapy deals with the unblocking of the suppressed immune system and activating the functioning of T-lymphocyte within the lymph node, which gets translated to an effective immune response against TNBC.

10.1. PD-L1

Programmed cell death (PD-1) receptor along with its ligand PD-L1 have been identified as biomarkers, because they are overexpressed in TNBC more than in any other type of breast cancer [[65],[66]]. The concept of immunotherapy lies in the fact that sometimes cancerous cells escape recognition as well as avoid destruction from the host immune system because of the immune checkpoint system, which provides ample opportunities for the cancerous cells to grow, migrate, invade, proliferate, and metastasize. In such cases, immunotherapy plays a vital part in blocking the immune checkpoint system, thus providing a therapeutic and effective antitumor immunity [[67]].
PD-1 is an inhibitory receptor belonging to the family of B7-CD28. PD-1 is overexpressed on the activated lymphocytes, non-lymphocytic cells like activated monocytes and dendritic cells, B-cells, and natural killer cells [[68]]. PD-1 is comprised of two ligands, PD-L1, and PD-L2, out of which PD-L1 is overexpressed in cancer cells, tumor-infiltrating lymphocytes, fibroblasts, and macrophages [[68], [69]]. In one of the studies, it was observed that statistically, about 45% of patients suffering from TNBC showed enhanced upregulation of both PD-L1 and PD-1, while 59% showed overexpression of PD-L1, and 70% showed overexpression of PD-1 [[70],[71]]. It was observed that the interaction of PD-1 to PD-L1, made the T-cells less active and form an inhibitory state, which provides a reduced immune response towards foreign antigens. This mechanism proved profitable to normal cells in preserving an immune balance and preventing an autoimmune response. However, this mechanism can lead to the detection of tumor cell evasion and elimination induced by the immune system [[72]]. Hence, it could be indicated that the PD-L1 positivity can be considered a TNBC biomarker that could be targeted via immune checkpoint inhibitor for better therapeutic response [[73]].

10.2. CTLA-4

CTLA-4 is an inhibitory receptor of T-cell, which is found to be overexpressed on activated CD8+ T cells [[74]]. Like PD-L, CTLA-4 also restricts the activation of T-cells by preventing its binding with its co-stimulatory molecules like CD80, and CD 86, resulting in detection of tumor cell evasion as well as its elimination by the immune system [[75]]. Hence, CTLA-4 also acts as a potential target against TNBC.

11. CSPG4 Proteins

CSPG4 is a proteoglycan, situated on the cell surface and found to be overexpressed in both melanoma cells and TNBC cells. It is also referred to as a melanoma-associated antigen or melanoma chondroitin sulfate proteoglycan [[76]]. CSPG4 protein spreads over the endothelial basement membrane, stabilizing the interaction between cell-substratum and resulting in events like cellular growth and proliferation, angiogenesis, and metastasis [[77]].

12. Androgen Receptor (AR)

ARs belong to the family of nuclear steroid hormone receptors [[78]]. The activation of AR is conducted by either the ERK-dependent pathway or the ERK-independent pathway. The ERK-dependent pathway includes the interaction of cytoplasmic AR with proteins like PI3K, Ras GTPase, and Src proteins, whereas the ERK-independent pathway involves phosphorylation of mTOR, activation of PKA, and inactivation of forkhead box protein O1 (FOXO1). Both the activation pathways ultimately result in cellular proliferation, EMT, angiogenesis, and metastasis [[79],[80]]. It was observed in a clinical study that 25–75% of TNBC progression is due to overexpression of AR, mostly in the LAR subtype of TNBC [[81],[82]]. In ASCO annual meeting, 2017, an investigation on AR expression in patients with TNBC showed that ≈30% of the patients were found to have positive AR expression [[37]]. Hence, it is contemplated that targeting AR may provide a potential platform for the treatment of TNBC.
Hence, from the above findings, it was observed that before providing proper treatment, one must identify the targets, which may be either proteins (CSPG4, Src Kinases), signaling pathways (Notch, hedgehog, Wnt-β, TGF-β, PI3K/AKT/mTOR), receptors (EGFR, IGF1R, AR, PD-1, CTLA-4) or enzymes (PARP1). It was observed that deregulation of these targets leads to TNBC progression. So, if one can identify those targets responsible for the progression, then their deregulation can be restricted or minimized, which will further reduce the risk of cancer growth. Moreover, based on the identifiable targets, various novel treatment options are under development. 

This entry is adapted from the peer-reviewed paper 10.3390/ph15050542

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