Pin1-based diagnostic and therapeutic strategies for breast cancer

Pharmacological Research 93 (2015) 28–35

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Perspective

Pin1-based diagnostic and therapeutic strategies for breast cancer夽 Jing-Zhang Wang ∗ , Bao-Guo Liu, Yong Zhang Department of Medical Technology, Affiliated Hospital, College of Medicine, Hebei University of Engineering, Handan 056002, PR China

a r t i c l e

i n f o

Article history: Received 5 October 2014 Received in revised form 19 December 2014 Accepted 19 December 2014 Available online 30 December 2014 Keywords: Breast cancer Pin1 Diagnostic strategy Therapeutic strategy

a b s t r a c t Pin1 is the only known cis-to-trans isomerase that recognizes the phosphorylated pThr/pSer-Pro motifs in many signaling molecules, playing unique roles in the pathogenesis of breast cancer. First, Pin1 is prevalently over-expressed in kinds of breast cancer cell lines and tissues, such as MDA-MB-231 cell, MCF-7 cell, Her2+, ER␣+, and basal-like breast cancer subtypes. Second, Pin1 amplifies many oncogenic signaling pathways, inhibits multiple tumor suppressors, promotes the angiogenesis and metastasis of breast cancer cells, and enhances the resistance of breast cancer cells to anti-tumor medicines. Third, inhibiting Pin1 blocks most of these detrimental effects in a great number of breast cancer cell lines. These findings suggest Pin1 as a promising diagnostic biomarker as well as an efficient therapeutic target for breast cancer. It is strongly expected that a Pin1-positive subtype of breast cancers should be extremely concerned and that the therapeutic efficacy of Pin1 inhibitors on breast cancer patients should be evaluated as soon as possible. Nonetheless, Pin1-based therapeutic strategies for breast cancer still deserve some debates. Hence, we give the predictions of several important issues, such as application precondition, side effects, and personalized medication, when Pin1 inhibitors are used in the breast cancer therapy. These proposals are meaningful for the further development of Pin1-based diagnostic and therapeutic strategies in order to conquer breast cancer. © 2014 Elsevier Ltd. All rights reserved.

Introduction Breast cancer endangers the health of human beings across the world [1,2]. Screening predictive biomarkers and targeting pathological molecules are very important to prevent breast cancer [3–5]. The reversible phosphorylation of serine or threonine preceding a

Abbreviations: Pin1, the peptidyl-prolyl cis-trans isomerase; SRC-3/AIB1, steroid receptor coactivator 3; FAK, focal adhesion kinase; Mcl-1, myeloid cell leukemia-1; p70S6K, ribosomal S6 kinase; Stat3, signal transducers and activators of transcription 3; PKB/Akt, serine/threonine protein kinase B; ER␣, estrogen receptor-alpha; ErbB2/HER2/neu, human epidermal growth factor receptor 2; Bax, Bcl-2-associated X protein; FOXO4, forkhead box O 4; RUNX3, runt-related transcription factor 3; Daxx, protein death domain-associated protein; RAR␣, retinoic acid receptor ␣; ATRA, all-trans retinoic acid; SMRT, silencing mediator for retinoic acid and thyroid hormone receptor; SUV39H1, suppressor of variegation 3–9 homologue 1; PML, promyelocytic leukemia protein; AP-1, activator protein-1; VEGF, vascular endothelial growth factor; DAPK1, death-associated protein kinase 1; PIN1, the gene encoding Pin1. 夽 Perspective articles contain the personal views of the authors who, as experts, reflect on the direction of future research in their field. ∗ Corresponding author at: Department of Medical Technology, Affiliated Hospital, College of Medicine, Hebei University of Engineering, 81# or 83# Cong Tai Road, Handan 056002, Hebei Province, PR China. Tel.: +86 0310 8575130; fax: +86 0310 8575130. E-mail addresses: [email protected], [email protected] (J.-Z. Wang). http://dx.doi.org/10.1016/j.phrs.2014.12.005 1043-6618/© 2014 Elsevier Ltd. All rights reserved.

proline (Ser/Thr-Pro) in proteins is an important signaling switch in diverse human diseases including breast cancer. Several previous reviews have well demonstrated that the peptidyl-prolyl cis-trans isomerase Pin1 is the only known isomerase that specifically catalyzes the phosphorylated pThr/pSer-Pro motifs form cis-configuration to trans-configuration, that Pin1 regulates the transcriptional efficiency, expression levels, function, subcellular localization, stabilization, ubiquitylation, and degradation of many signaling molecules, and that Pin1 plays a vital role in a number of human diseases especially cancers and neurodegenerative disorders [6–9]. Our recent studies revealed the linking role of Pin1 in several chronic human diseases, too [10,11]. In this perspective, we focus on the increasing evidence that uncovers the vital role of Pin1 in the pathogenesis of breast cancer, and we further emphasize the importance of Pin1-based diagnostic and therapeutic strategies for the prevention of breast cancer.

The essential role Pin1 in the pathogenesis of breast cancer The activation of multiple oncogenes and growth enhancers by Pin1 Pin1 activates more than two dozens of oncogenes and growth enhancers relevant to breast cancer, which is briefly shown in

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Table 1 Positive effects of Pin1 on multiple oncogenes and growth enhancers relevant to breast cancer. Oncogenes/growth enhancers

Roles in breast cancer

Binding motifs for Pin1

Function of Pin1

References

AIB1/SRC-3

Activates estrogen receptor and progesterone receptor; Leads to the development and progression of hormone-dependent and -independent breast cancer. Associates with disease development, poor prognosis, lower patient survival, and resistance to radiotherapy in breast cancer. Mediates Wnt signaling pathway; Promotes the proliferation, invasion, and metastasis of breast cancer. Composes the hetero-dimeric activator protein-1 (AP-1); Facilitates the nuclear import of some oncoproteins in breast cancer cell.

pSer505

Promotes the cooperation of AIB1 and other coactivators.

[7,14,32–34]

pThr92; pThr450

Increases Akt stability; Protects Akt from degradation.

[26,35]

pSer246

Inhibits ␤-catenin degradation; Enhances the nuclear accumulation and stabilization of ␤-catenin. Potentiates the transcriptional response of c-Fos and AP-1 to multiple growth factors.

[13,27,36,37]

Increases the transcriptional activity of c-Jun toward downstream genes including cycling D1. Enhances the binding of c-Myc and its coactivators to DNA promotors; Promotes c-Myc to activate the genes involved in cell growth, metabolism, and proliferation. Up-regulates the expression and the function of cyclin D1 via multiple signaling pathways; Increases the nuclear localization of cyclin D1; Stabilizes cyclin D1. Increases ER␣ levels by inhibiting the proteasome-dependent degradation of it.

[13,16,40]

–

Attenuates the ubiquitin-mediated degradation of ErbB2; Increases the stability and cellular levels of ErbB2.

[30,46–49]

pSer910

Promotes the dephosphorylation of FAK.

[19,50–52]

pThr92; pThr163

Stabilizes Mcl-1; Up-regulates the cellular levels of Mcl-1.

[20,53,54]

pSer52; pSer65

Stabilizes Nanog by suppressing its ubiquitination and degradation.

[31,55]

pThr254

Increases the nuclear accumulation and the protein stability of p65, which is a major component of the heterodimeric NF-␬B; Enhances the activity ofNF-␬B. Modifies the structure of Notch1; Facilities the generation of the active intracellular domain of Notch1; Enhances the transcriptional activity of Notch1. Enhances the phosphorylation of p70S6K; Activates p70S6K-mediated signaling pathways. Hyperphosphorylated Raf-1 is inactive, but Pin1 promotes the dephosphorylation of Raf-1 by PP2A and recycles Raf-1 to its active form.

[7,13,21]

Promotes the activity of Stat3 and the expression of its target genes.

[25,60,61]

Akt/PKB

␤-Catenin

c-Fos

c-Jun

c-Myc

Composes the hetero-dimeric AP-1; Promotes the invasion and migration of breast cancer cell. Promotes the proliferation and invasion of breast cancer cell; Correlates with the poor outcome of breast cancer.

Possibly pThr232; pThr325; pThr331; pSer374 pSer63; pSer73 pSer62

Cyclin D1

Promotes the proliferation, migration, and invasion of breast cancer cell; Serves as a diagnostic biomarker for breast cancer.

pThr286

ER␣

Functions as a hormone-regulated transcription factor; Critical for the efficiency of endocrine therapy. Promotes the proliferation and growth of breast cancer cell; Acts as a transcriptional coactivator for Stat3, cyclin D1, etc.; Is an independent prognostic factor of poor clinical outcome in MembErbB2+ breast cancer. Significantly correlates with basal-like/triple negative breast cancer; Critical for the metastasis of breast cancer. Increases the viability of breast cancer cell; Contributes to the proliferation and migration of breast cancer cell; Resist to cell apoptosis; Blocks the chemo-sensitization of breast cancer cell. Is a transcriptional factor maintaining the pluripotency of breast cancer cell; Promotes the proliferation of breast cancer cell. Up-regulates many genes involved in antiapoptosis, proliferation, angiogenesis, and metastasis of breast cancer cell.

pSer118

ErbB2(Her2/neu)

FAK

Mcl-1

Nanog

NF-␬B

Notch1

Is over-activated in about 50% of breast cancer; Is a therapeutic target for breast cancer.

pSer2122; pThr2133; pSer2137

p70S6K

Significantly associates with the tamoxifen resistance and the prognosis in ER␣+ postmenopausal breast cancer. Blocks the drug-sensitivity of breast cancer cell; Contributes to the drug-resistance of breast cancer cell; Enhances the expression of HER-2/Neu and leads to the distant metastases in ER␣+ breast cancer. Acts as an oncogene and is constitutively activated in various breast cancer cell lines; Associates with the proliferation, migration, drug resistance, and epithelial-mesenchymal transition of breast cancer cell.

pThr389

Raf-1

Stat3

Possibly pSer642

pSer727

[15,38,39]

[17,41,42]

[18,28,43–45]

[29]

[7,22]

[23,56]

[24,57–59]

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Table 1. These oncogenes and growth enhancers play important roles in the multiple stages of breast cancer, such as tumor initiation, subtype classification, proliferation, invasion, migration, metastasis, drug-resistance, poor prognosis, low survival rate, and so on. The activation of each oncogenesis signaling is mainly due to the binding of Pin1 to one or more specific pThr/pSer-Pro motifs in the related proteins, and subsequently Pin1 modifies their structures and leads to (directly or indirectly) accelerated dephosphorylation, enhanced stability, increased activity, facilitated subcellular localization, decreased degradation, strengthened interaction with downstream effectors, and so on [6–8,12,13]. For example, Pin1 increases the activity of steroid receptor coactivator 3 (SRC-3/AIB1), c-Fos, c-Jun, c-Myc, cyclin D1, focal adhesion kinase (FAK), myeloid cell leukemia-1 (Mcl-1), NF-␬B, Notch1, ribosomal S6 kinase (p70S6K), Raf-1, and signal transducers and activators of transcription 3 (Stat3) [7,8,14–25]. Pin1 enhances the stability of serine/threonine protein kinase B (PKB/Akt), ␤-catenin, c-Jun, cyclin D1, estrogen receptor-alpha (ER␣), human epidermal growth factor receptor 2 (ErbB2/Her2/neu), Mcl-1, Nanog, and NF-␬B [16,18,20,21,26–31]. Pin1 up-regulates the transcriptional activity of c-Fos, c-Jun, c-Myc, NF-␬B, Notch1, and Stat3, and Pin1 also facilitates the subcellular localization of ␤-catenin, cyclin D1, ErbB2, NF-␬B, and Notch1, and so on [6–8,13,27]. Nevertheless, many other potential effects of Pin1 on the development of breast cancer still need to be further explored in the future. The inactivation of multiple tumor suppressors and growth inhibitors by Pin1 Pin1 inactivates many tumor suppressors and growth inhibitors relevant to breast cancer, which is briefly shown in Table 2. It can be seen that these tumor suppressors and growth inhibitors have potent inhibitory effects on the proliferation, development, invasion, and migration of breast cancer cell, and some of them can sensitize breast cancer cell to anti-tumor drugs such as tamoxifen. Unfortunately, Pin1 inactivates Bcl-2-associated X protein (Bax), forkhead box O 4 (FOXO4), Pin2/TRF1, runt-related transcription factor 3 (RUNX3) [62–65]. Pin1 decreases the stability (or increases the degradation) of Bcl-2, protein death domain-associated protein (Daxx), Fbw7, retinoic acid receptor ␣ (RAR␣), silencing mediator for retinoic acid and thyroid hormone receptor (SMRT), Smad2/3, RUNX3, suppressor of variegation 3–9 homologue 1 (SUV39H1), and promyelocytic leukemia protein (PML) [7,8,65–73]. Pin1 also blocks the subcellular localization of Bax, Bcl-2, FOXO4, and so on [62,63,66]. In addition, it seems a little complicated to describe the regulation of p53 by Pin1. Previous studies have shown that Pin1 up-regulates the transcriptional activity and the stability of p53 [74–76]. However, higher Pin1 activity is prone to cause the monoubiquitylation of p53 and consequently triggers the downstream signaling transduction, while lower Pin1 activity stimulates the poly-ubiquitylation and the consequent degradation of p53 [77]. Additionally, Pin1 interacts with mutated p53 and thus promotes the aggressiveness of breast cancer cell lines, and Pin1 disrupts the prognostic value of p53 in cancer therapy [78,79]. Pin1 promotes the angiogenesis and distant metastasis of breast cancer cell Pin1 is associated with the migration and the metastasis of breast cancer cell via inducing angiogenesis. First, Pin1 up-regulates the transcription and the expression of vascular endothelial growth factor (VEGF) and induces the VEGF-mediated angiogenesis and metastasis of breast cancer cell [97–99]. The induction of VEGF by Pin1 also enhances the resistance of breast cancer cell to anti-estrogen therapy [100]. Second, Pin1 was recently shown

to up-regulate the mRNA level and the protein expression of transforming growth factor-beta (TGF-␤) [101]. TGF-␤ potentially mediates the epithelial-mesenchymal transition, lung metastasis, and bone metastasis of breast cancer cell [102–104], and could be a predictor of distant metastasis of breast cancer cell [105]. Third, hypoxia-inducible factor-1 (HIF-1) promotes tumor angiogenesis and metastasis via multiple cellular mechanisms, including the induction of VEGF transcription [106]. Pin1 was recently shown to regulate the stability of HIF-1␣ [107], which is one of the two subunits of the heterodimeric transcription factor HIF-1 [106].

Pin1 may be an efficient diagnostic and prognostic biomarker for breast cancer In our previous work, it has been expounded that some factors in vivo potentially influence Pin1 expression and Pin1 activity, so these factors, especially the polymorphisms of PIN1 gene (encoding Pin1 protein), may be implicated in the development of breast cancer [10,11]. Notably, the genetic polymorphisms of PIN1 promotor influence the transcriptional efficiency, mRNA splitting, protein expression, and enzymatic activity of Pin1 [108–111]. Take the −842G/C polymorphism of PIN1 gene for example, it is showed that the women carrying the −842G allele have higher incidence of breast cancer when compared to those carrying the −842C allele [112], which is mainly attributed to the higher transcriptional activity of PIN1 gene and the higher expression of Pin1 protein caused by the −842G allele [110,113]. Beside, the −667T/C and −5185G/C polymorphisms of PIN1 gene are correlated with the function of Pin1 and potentially the pathogenesis of breast cancer, too [109,114]. On the other hand, several transcription factors, such as E2F [100,115,116], Notch1 [22], and insulin-like growth factor I [117], can induce the transcription of PIN1 gene and enhance Pin1 expression. By contrast, death-associated protein kinase 1 (DAPK1) significantly inhibits the cellular activity of Pin1 by phosphorylating Ser71 that is located in the catalytic active site of Pin1, but loss of DAPK1 hinders the phosphorylation of Pin1 on Ser71 and leads to the up-regulated activity of Pin1 in a few of breast cancer cell lines and tissues [118,119]. In addition, post-translational modifications, cellular acidification, and some physical and chemical factors might influence Pin1 function in vivo [11,120,121]. As a result, the over-expression and the over-activity of Pin1 will potentially alter a series of downstream signaling pathways, significantly contributing to the pathogenesis of breast cancer. Actually, Pin1 is frequently over-expressed in a wide variety of breast cancer cell lines, such as MDA-MB-231 cell [22,26], MDA-MB-468 [22,26], and MCF-7 especially tamoxifen-resistant (TAMR)-MCF-7 cell lines [22,100,122,123]. Pin1 is also highly expressed in many primary and metastatic tissues of breast cancers, including Her2+ [30], ER␣+ [123], and basal-like breast cancers [124]. Further, Pin1 overexpression in breast cancer cell is often accompanied by the overexpression of oncogenesis proteins such as Akt [26], c-Myc [17], Her2/Neu [30,125], ␤-catenin [27], cyclin D1 [16,126], Notch1 [22], Stat3 [25], ER␣ [123], and Mcl-1 [20], and is also correlated with the inactivation of tumor suppressors such as FOXO4 [63], PML [72], RUNX3 [65], SUV39H1 [71], and so on. Pin1 overexpression also triggers the epithelial-mesenchymal transition and expands the growth and tumorigenicity of breast cancer stem cells [127,128]. Because of their implications in breast cancer, most of the molecules mentioned above are suggested as biomarkers for breast cancer. However, we must pay attention to the central role of Pin1 in regulating all of these molecules, which potentially enables Pin1 to be an extremely important biomarker for predicting the cell initiation, proliferation, transformation, tumor stages, metastasis, angiogenesis, drug sensitivity, reoccurrence, and survival rate of breast cancer [17,20,26,30,127,129].

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Table 2 Negative effects of Pin1 on multiple tumor suppressors and growth inhibitors relevant to breast cancer. Tumor suppressors/growth inhibitors

Roles in breast cancer

Binding motifs for Pin1

Function of Pin1

References

Bax

Is involved in the apotosis of breast cancer cell.

pThr167

[62,80,81]

Bcl-2

Is involved in the apotosis of breast cancer cell.

pSer87

Daxx

Is an essential nuclear protein involved in the mitotic progression, transcriptional regulation, apoptosis, and taxane sensitivity of breast cancer cell. Recognizes and binds phosphorylated substrates of the Skp1-Cullin-F-box type E3 ligase complex; Down-regulates numerous oncoproteins; Suppresses the proliferation of breast cancer cell. A member of the FOXO family that is a subclass of tumor suppressors.

pSer178

Prevents the activation of Bax and the translocation of Bax to the mitochondria. Promotes the dephosphorylation of Bcl-2 in the nucleus; Dephosphorylated Bcl2 inside the nucleus loses the anti-apoptotic function possibly because of its inability to relocate to the mitochondria. Promotes the rapid degradation of Daxx by the ubiquitin-proteasome system.

pThr205

Disrupts the dimerization of Fbw7; Promotes the ubiquitination and degradation of Fbw7.

[73,84,85]

Possibly pThr447; pThr451; pThr223; pSer226 pSer33; pThr81; pSer315

Down-regulates the transcriptional activity of FOXO4; Decreases the nuclear translocation of FOXO4.

[63,86,87]

Modulates the conformation of p53; Enhances the activity of p53; Stabilizes p53; Triggers the poly-ubiquitylation and the degradation of p53. Destabilizes RAR␣ in a ligand independent-manner; Induces the degradation of RAR␣ via the proteasome-dependent pathway.

[74,77,88–90]

pSer1241; pThr1445; pSer1469

Decreases the protein stability of SMRT; Blocks the SMRT-dependent transcriptional repression.

[69,93]

Unknown

Negatively regulates Smad2/3 levels by inducing their ubiquitin-proteasomal degradation. Inhibits TRF1 to regulate the length of telomere.

[70,94–96]

Suppresses the transcriptional activity of RUNX3; Reduces the cellular concentration of RUNX3 by inducing its ubiquitination and proteasomal degradation. Promotes the ubiquitination-mediated degradation of SUV39H1.

[65]

Regulates the structure of PML; Enhances the degradation of PML.

[72]

Fbw7

FOXO4

p53

RAR␣

SMRT

Smad2/3

TRF1/Pin2

RUNX3

SUV39H1

PML

A potent tumor suppressor implicated in several breast cancer subtypes; A predictor for the recurrence of breast cancer; Influences the drug sensitivity in breast cancer therapy. Is over-expressed in about 30% of ErbB2+ breast cancers; Determines the sensitivity of ER+ breast cancer cell and the refractoriness of ER− breast cancer cell to all-trans retinoic acid (ATRA) and its derivatives (retinoids). A transcriptional corepressor of many signaling pathways in breast cancer; Sensitizes breast cancer cells to the treatment with tamoxifen. Regulates multiple target genes relevant to breast cancer. A key telomeric protein maintaining the optimal telomere length and the cellular proliferative capacity. An important tumor suppressor in breast cancer; Its inactivation results in the initiation and progression of breast cancer.

A major methyltransferase responsible for the histone H3 trimethylation; Prevents the tumorigenesis in breast. An important tumor suppressor because of its role in regulating cell cycle, DNA damage, and apoptosis.

First, analyzing the genetic polymorphisms of PIN1 promotor by PCR-RFLP, DNA sequencing, TaqMan probe assay, and gene microarray may be helpful for screening the individuals who have higher risk of breast cancer incidence, refractory, and reoccurrence [112,130]. Second, measuring the mRNA level of Pin1 by real-time quantitative PCR may benefit the clinical therapy of different breast cancer subtypes, for instance, Pin1 mRNA is significantly higher in basal-like breast cancer than in luminal breast cancer [17,124]. Third, immunohistochemical staining and immunoblotting analysis are useful for determining Pin1 over-expression in breast cancer tissues [71,97,116,129]. Last but not the least, serum Pin1 may be an important indicator because of its predictive potency and convenient detection by the available enzyme-linked immunosorbent assay (ELISA) [131,132].

pSer77

pThr149

pThr209; pThr212; pThr231; pSer214 pSer391

Possibly pSer403; pSer505; pSer518; pSer530

[66,81–83]

[67]

[68,91,92]

[64]

[71]

Inhibiting Pin1 has potentially striking therapeutic efficacy on breast cancer Pin1 inhibition, by gene knockout, inhibitors, or small interfering RNA, attenuates oncogenic factors such as Akt [26], Her2/Neu [30], ␤-catenin [27], cyclin D1 [16,126], Notch1 [22], and VEGF-mediated angiogenesis [97,99], and enhances the levels of tumor suppressors such as RUNX3 [65], SUV39H1 [71], PML [133], SMRT [133], and so on. Consequently, Pin1 inhibition prevents the massive proliferation and transformation of breast epithelial cell [115,134], and suppresses the growth and proliferation of Her2+ [30], BT-474 [133], MCF-7 [125,135], TAMR-MCF-7 [97,116,122], and BT20 breast cancer cell lines [21,65,136].

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Fig. 1. The perspective application of Pin1-based diagnostic and therapeutic strategies in the breast cancer therapy.

Especially, Pin1 inhibition reduces the Her2-induced transforming phenotypes [6,52] and increases the drug sensitivity of Her2+ breast cancer cells [30]. Pin1 over-expression is significantly enriched in the triple negative and Her2+ breast cancer subtypes when compared to luminal A subtype, and it is correlated with poorer outcome of Her2+ and basal breast cancers compared to luminal A breast cancer [17,124]. Therefore, Pin1 inhibition might have more significant therapeutic efficacy on Her2+ and basal breast cancers than luminal A cancer. Besides, Pin1 silencing inhibits the expansion, self-renewal activity, and tumorigenesis of breast cancer stem cell in vitro and in vivo [128]. All of these findings guarantee Pin1 as a promising therapeutic target for the breast cancer therapy. In recent years, the therapeutic potency of Pin1 inhibitors has been evaluated in many laboratories [137–139]. On one hand, some Pin1 inhibitors were extracted from natural plants. For example, decursin, which was extracted from Angelica gigas, exerted inhibitory effect on breast cancer cell by blocking the activity of Pin1 [137]. Amurensin G blocked Pin1 and had therapeutic efficacy on breast cancer cell [116]. Gallate, a major flavonoid in green tea, was identified to blockade Pin1, too [140]. On the other hand, structureguided Pin1 inhibitors were synthesized by chemists. For example, Pin1 inhibitors designed with a phenyl imidazole acid core blocked the activity of Pin1 [141]. Several cyclohexyl ketone analogs were synthesized, and they chelated the active center of Pin1 [142]. Some benzophenone derivatives also displayed high inhibitory activity on Pin1 [143]. These results shed light on the further design and optimization of novel Pin1 inhibitors and expand their potential application in the field of the breast cancer therapy. Rational administration of Pin1 inhibitors for the breast cancer therapy Although Pin1 inhibition has shown potent anti-breast cancer effects in vitro and in vivo, several important points need to be discussed before the clinical application of Pin1 inhibitors. Especially, because breast cancer has many heterogeneous characteristics such as luminal A, luminal B, Her2+, and basal-like subtypes [50], a rational use of Pin1 inhibitors in the clinic requires the screening of patients that would potentially be benefited by Pin1-based therapeutic approaches. Suitable breast cancer indications for Pin1 inhibitors Pin1 inhibitors may conquer breast cancer mainly because Pin1 is over-expressed in kinds of breast cancer tissues. However, it should be noted that the distribution of Pin1 is varied in

different cell lines and tissues [144]. Consequently, it is speculated that Pin1 inhibitors may only benefit the breast cancer patients with pathological over-expression of Pin1, while those with normal or down-regulated expression of Pin1 are not suitable individuals for the treatment with Pin1 inhibitors. It is strongly suggested that the pathological examinations must be carried out to confirm the over-expression of Pin1 in breast cancer tissues by means of immunohistochemical assay, real-time quantitative PCR, and other available methodologies before the administration of Pin1 inhibitors. Otherwise, false application of Pin1 inhibitors may cause serious side effects. Side effects potentially caused by Pin1 inhibitors The medicines for cancer therapy often cause some side effects especially neurocognitive damage and cardiovascular toxicity [145]. As we have mentioned before, Pin1 plays an indispensable role in preventing Alzheimer’s disease, hypertension, cerebral amyloid angiopathy, and so on [10,146], so Pin1 inhibitors may result in neurological damage and cardiovascular disorders, too. These side effects can be tolerated compared to the clinical benefits for breast cancer patients, but doctors must ensure that these side effects are allowable and controllable. To minimize the potential side effects, Pin1 inhibitors should only be applied in hospitals where it is easily to monitor the pathological indicators of neurodegenerative and cardiovascular disorders. Then, doctors evaluate the clinical benefits for breast cancer and the side effects, and decide whether the treatment with Pin1 inhibitors should be continued or not. In a word, Pin1 should be inhibited appropriately, but not completely, in order to achieve maximum therapeutic efficacy on breast cancer as well as minimum side effects. Personalized medication of Pin1 inhibitors for breast cancer As mentioned above, the −842G/C, −667T/C, and −5185G/C polymorphisms of PIN1 gene may not only influence the predictive efficiency of Pin1 as a biomarker but also interfere with the therapeutic efficacy of Pin1 inhibitors, calling for personalized medication with optimized dose of Pin1 inhibitors in the breast cancer therapy. Briefly, the polymorphisms of PIN1 gene in breast cancer patients should be analyzed before the treatment. For instance, higher dose of Pin1 inhibitors are needed by the −842G allele carriers who have potentially higher expression and activity of Pin1 in vivo, while lower dose of Pin1 inhibitors should be applied to the −842C allele carriers who have potentially lower expression and activity of Pin1. According to the relevant research, the aim of

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the personalized medication is to achieve maximum therapeutic efficacy and minimum side effects based on the analysis of PIN1 genotypes in breast cancer patients. Conclusions As shown in Fig. 1, the multiple roles of Pin1 make it possible to conquer a large number of breast cancers, especially Her2+, ER␣+, and basal-like breast cancers, by Pin1-based diagnostic and therapeutic strategies. It is strongly proposed that the breast cancer with Pin1 over-expression (Pin1-positive or Pin1+) may represent a new and typical subtype of breast cancers, which deserves to be further studied and treated separately in the near future. In summary, Pin1, used as a diagnostic and prognostic biomarker, may greatly improve the early prevention, clinical therapy, and reoccurrence prediction of breast cancer. Pin1 inhibitors, extracted from natural plants by biologists or synthesized artificially by chemists, may efficiently benefit the breast cancer patients that have the up-regulated expression and activity of Pin1. Especially, patients with the early-stage breast cancer are willing to be benefited because of the sensitivity of Pin1-based diagnostic strategy and the efficacy of Pin1-based therapeutic strategy. Conflict of interest statement The authors declare no conflict of interest. Acknowledgments This work was supported by the fundings from Hebei Educational Committee of China (no. QN20131051) and Handan Science and Technology Department of China (no. 1223108086-4). References [1] Durmus S, Xu N, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) restrict brain accumulation of the JAK1/2 inhibitor, CYT387. Pharmacol Res 2013;76:9–16. [2] Piotrowski G, Gawor R, Bourge RC, Stasiak A, Potemski P, Gawor Z, et al. Heart remodeling induced by adjuvant trastuzumab-containing chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2: a prospective study. Pharmacol Res 2013;78:41–8. [3] Roskoski Jr R. ErbB/HER protein-tyrosine kinases: structures and small molecule inhibitors. Pharmacol Res 2014;87:42–59. [4] Soriano A, Jubierre L, Almazan-Moga A, Molist C, Roma J, Sanchez de Toledo J, et al. microRNAs as pharmacological targets in cancer. Pharmacol Res 2013;75:3–14. [5] Yao Z, Hu W, Yin S, Huang Z, Zhu Q, Chen J, et al. 3,3 -Diindolymethane ameliorates adriamycin-induced cardiac fibrosis via activation of a BRCA1dependent anti-oxidant pathway. Pharmacol Res 2013;70:139–46. [6] Lu KP, Zhou XZ. The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol 2007;8:904–16. [7] Lee TH, Pastorino L, Lu KP. Peptidyl-prolyl cis-trans isomerase Pin1 in ageing, cancer and Alzheimer disease. Expert Rev Mol Med 2011;13:e21. [8] Liou YC, Zhou XZ, Lu KP. Prolyl isomerase Pin1 as a molecular switch to determine the fate of phosphoproteins. Trends Biochem Sci 2011;36:501–14. [9] Driver JA. Understanding the link between cancer and neurodegeneration. J Geriatr Oncol 2012;3:58–67. [10] Wang JZ, Zhang YH, Sun XW, Li YL, Li SR, Zhang Y, et al. Focusing on the structure and the function of Pin1: new insights into the opposite effects of fever on cancers and Alzheimer’s disease. Med Hypotheses 2013;81:282–4. [11] Wang JZ, Li SR, Li YL, Zhang YZ, Zhang T, Zhao CX, et al. Could Pin1 help us conquer essential hypertension at an earlier stage? A promising earlydiagnostic biomarker and its therapeutic implications for the disease. Med Hypotheses 2013;81:931–5. [12] Driver JA, Lu KP. Pin1: a new genetic link between Alzheimer’s disease, cancer and aging. Curr Aging Sci 2010;3:158–65. [13] Lu KP. Pinning down cell signaling, cancer and Alzheimer’s disease. Trends Biochem Sci 2004;29:200–9. [14] Yi P, Wu RC, Sandquist J, Wong JM, Tsai SY, Tsai MJ, et al. Peptidyl-prolyl isomerase 1 (Pin1) serves as a coactivator of steroid receptor by regulating the activity of phosphorylated steroid receptor coactivator 3 (SRC-3/AIB1). Mol Cell Biol 2005;25:9687–99.

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