Pin1-based diagnostic and therapeutic strategies for breast cancer

doi:10.1016/j.phrs.2014.12.005

Pharmacological Research

Volume 93, March 2015, Pages 28-35

https://doi.org/10.1016/j.phrs.2014.12.005 Get rights and content

Abstract

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+, ERα+, 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.

Graphical abstract

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], [4], [5]. The reversible phosphorylation of serine or threonine preceding a 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], [7], [8], [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.

Section snippets

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 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

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], [109], [110], [111]. Take the −842G/C polymorphism of

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], β-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

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.

Conclusions

As shown in Fig. 1, the multiple roles of Pin1 make it possible to conquer a large number of breast cancers, especially Her2+, ERα+, 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

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).

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With the introduction of a series of inhibitors to BC, the development and clinical application of new selective antitumor drugs have attracted great attention. The phosphorylated silk/threonine (psER/Thr-Pro) gene sequences are a crucial signaling mechanism for the occurrence and growth of breast cancer [10,11]. They are intimately associated with cell proliferation and differentiation.
Developing chemotherapy with nanoparticle-based prodrugs provides promising strategies for improving the safety and delivery of anti-cancer drugs therapeutics and effective cancer treatment. Herein, we developed a pH-sensitive prodrug delivery system (All-Trans-Retinoic Acid (ATRA) grafted poly (β-amino esters) (PBAE) copolymers, ATRA-g-PBAE) for delivery of ATRA with some physicochemical and biological properties. The in vitro release of ATRA-g-PBAE prodrug nanoparticles (PNPs) was sustained-release and pH-sensitive. The cytotoxicity and uptake of different preparations in vitro were evaluated on MCF-7 cells at pH 7.4 and 5.5. The carrier PBAE had no cytotoxicity, and ATRA-g-PBAE PNPs could significantly inhibit cell growth at pH 5.5. MCF-7 cells treated with Cy5.5 grafted PBAE (Cy5.5-PBAE) showed stronger fluorescence signals at pH 5.5. Meanwhile, ATRA-g-PBAE PNPs entered the cell via a clathrin-mediated endocytic pathway. Subsequently, PBAE protonation facilitated the escape of PNPs from the lysosome and released the drug. ATRA-g-PBAE seems promising as a novel pH-sensitive prodrug to overcome the limitations of ATRA for breast cancer therapy.
A preliminary identification of PIN1 SNP linkage in patients with coronary heart disease from Handan, China
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However, many people without these unhealthy lifestyles and dietary habits still suffer from CHD, so researchers are paying more attention to genetic differences in CHD patients.1–5 Pin1, encoded by the PIN1 gene, regulates phosphorylation of proteins and is implicated in human diseases.6–11 Our recent research predicted that (i) Pin1 may promote cardiovascular disease by suppressing endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO) in blood vessels,7 (ii) a potential glucose-Pin1-eNOS-NO pathway may lead to coronary atherosclerosis in diabetic patients,12 and (iii) serum Pin1 may be associated with CHD and hypertension.11
Our aim was to perform an initial assessment of the polymorphic patterns of the PIN1 gene in patients with coronary heart disease (CHD). The PIN1-encoded protein (Pin1) suppresses eNOS-NO signaling and may impair cardiovascular function. Blood collection, DNA extraction, PCR amplification and gene sequencing were performed for thirty CHD participants living in central China, focusing on nine single nucleotide polymorphisms (SNPs). Their genetic linkages were revealed and their allele frequencies were compared with SNP data from the NCBI. Three major linkage patterns were identified: [1.rs2287839-5.rs2233682], [3.rs2233679-4.rs1077220–8.rs2287838] and [6.rs889162-7.rs2010457], suggesting correlated involvement in CHD and possible simultaneous genetic origin in ancient times. The frequencies of six SNPs are consistent with the NCBI data, while the frequencies of three SNPs (2.rs2233678, 4.rs1077220 and 9.rs4804461) are not consistent with the NCBI. Especially, the 3.rs2233679–4.rs1077220 linkage is different from other populations worldwide and may be an interesting genetic characteristic of Chinese CHD patients. Predictably, 1.rs2287839, 2.rs2233678, 3.rs2233679 and 5.rs2233682 may be strongly associated with CHD risk, although this requires future verification. The PIN1 SNP linkages lay a new genetic foundation for discovering novel molecular mechanisms of CHD and for exploring PIN1-based targeted treatment of CHD with nitric oxide regulatory therapies in clinical practice.
O objetivo deste estudo é avaliar os polimorfismos do gene PIN1 em doentes com doença arterial coronária (DAC). A proteína codificada pelo gene PIN1 (Pin1) suprime a sinalização eNOS-NO e pode afetar a função cardiovascular. Foram incluídos 30 indivíduos com DAC, residentes na China central, a quem foi recolhido sangue, extraído e amplificado o DNA por PCR. Foram estudados nove polimorfismos de nucleótidos únicos (SNPs) do gene PIN1. As suas associações genéticas foram estudadas e as frequências de alelo foram comparadas com os dados de SNPs do NCBI. Foram identificados três grandes padrões de linkage: [1.rs2287839-5.rs2233682], [3.rs2233679-4.rs107220-8.rs2287838] e [6.rs889162-7.rs2010457], sugerindo o seu envolvimento na DAC e possível origem genética simultânea histórica. As frequências de seis dos SNPs foram consistentes com os dados do NCBI, enquanto as frequências de três dos SNPs (2.rs2233678, 4.rs1077220 e 9.rs4804461) não foram consistentes com o NCBI. Especificamente, a ligação 3.rs2233679-4.rs1077220 é diferente de outras populações mundiais e poderá constituir uma característica genética específica dos doentes chineses com DAC. Previsivelmente, 1.rs2287839, 2.rs2233678, 3.rs2233679 e 5.rs2233682 podem estar particularmente associados ao risco de DAC, requerendo validação ulterior. As ligações PIN1-SNP estabelecem uma nova base genética para a descoberta de novos mecanismos moleculares da DAC e para explorar o tratamento de precisão da DAC com medicamentos reguladores do óxido nítrico, baseado nos polimorfismos do gene PIN1.
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Vascular atherosclerosis leads to various cardiovascular and cerebrovascular diseases. Nitric oxide (NO) promotes vasodilatation and prevents Coronary Artery Disease (CAD). Pin1 suppresses NO production by down-regulating the activity of endothelial nitric oxide synthase (eNOS). Whether the genetic polymorphisms of the PIN1 gene (encoding Pin1) are implicated in CAD deserves investigations in human beings.
A total of 210 CAD patients and control individuals (all females) were enrolled, and their genotypes of rs2233679 (–667C/T, a key SNP in the promoter of PIN1 gene) were sequenced. T-test, chi-square test, odds ratio (OR) and 95% confidence interval (95% CI) were calculated to evaluate Hardy–Weinberg equilibrium, varied genetic distribution and relative CAD risk.
The differences in age, BMI, triglyceride, total cholesterol, low-density and high density cholesterol between the CAD and control groups were not significant (all P>0.05), and Hardy-Weinberg equilibrium was observed in the two groups (both P>0.05). The frequency of –667T allele in the CAD group was higher than that in the control group. The genotype –667TT elicited a higher hazardous risk of CAD compared to the genotype –667CC (OR=1.85, 95% CI: 0.75-4.53) as well as the genotypes CC+CT (OR=1.97, 95% CI: 0.86-4.49).
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On the other hand, PIN1 overexpression, a transcriptional coactivator of ER, has also been shown to stimulate the growth, tumorigenicity, and epithelial-mesenchymal transition in breast cancer,91 as well as hyperplasia and the formation of malignant mammary tumors in mouse mammary glands.59 Furthermore, PIN1 polymorphisms have also been associated with the development of breast cancer and with a poor clinical prognosis.60 In addition, PIN1 is targeted for breast cancer therapies with natural and synthetic inhibitors to control its activity.92-98
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Evidence shows that Pin1 activity is tightly regulated by transcriptional factors, mRNA splicing, and posttranslational modifications in different tissues, for example, the brain-selective transcription factor AP4 specifically regulates Pin1 expression in neural tissues; similar transcription factors might influence Pin1-regulated cellular responses in different animal models and cell lines [36–38]. We and others have stated that Pin1 directly regulates structures and functions of dozens of vital signaling molecules such as NF-κB, β-catenin, c-Jun/AP-1, Cyclin D1, and c-Myc, and Pin1 therefore has comprehensive influences on hundreds of molecules indirectly, including phosphorylases, dephosphorylases, transcriptional factors, and so on [21,23,24,39]. For example, we have ever described that Pin1, eNOS, and amyloid-β (Aβ) form a feedback signaling loop regulating the pathogenesis of hypertension [21], and Hariharan et al. regarded Pin1 as a molecular orchestrator or a molecular timer in cardiovascular signaling networks via regulating some key molecules in the heart [39–42].
Our lab focused on the structural and functional properties of Pin1, which is the only known cis–trans isomerase regulating pSer/pThr–Pro motifs in proteins and facilitates various signaling pathways. We are lucky enough to read the article, contributed by Costantino et al. in your esteemed journal, on the role of Pin1 in diabetes-induced vascular dysfunction. Pin1 regulates the production of nitric oxide (NO), which is a key physiological stimulator of blood vessels and promotes vascular relaxation responses significantly. However, the regulation of cardiovascular diseases by Pin1 is somewhat controversial.
We compared the recent studies that support the down-regulation, as well as up-regulation, of NO production by Pin1 and tried to explore the underlying molecular mechanisms. We especially compared the different regulations of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) by Pin1, which is potentially the major reason leading to the controversial role of Pin1. Interestingly, the regulation of both eNOS and iNOS by Pin1 involves a double-edge effect, positively and negatively, contributing to paradoxical Pin1 functions in different animal models and cell lines. The extremely complex Pin1-regulated signaling networks might further exacerbate distinct cellular responses in vivo and influence NO production.
Pin1 plays a dual role, both positive and negative, in regulating NO production and in mediating the pathogenesis of cardiovascular diseases. Pin1 functions may vary a lot under different circumstances. Future investigations should focus on eNOS as well as iNOS in order to increase authenticity and accuracy of results.
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View all citing articles on Scopus

^☆: Perspective articles contain the personal views of the authors who, as experts, reflect on the direction of future research in their field.

View full text

PerspectivePin1-based diagnostic and therapeutic strategies for breast cancer☆

Abstract

Graphical abstract

Introduction

Section snippets

The activation of multiple oncogenes and growth enhancers by Pin1

Pin1 may be an efficient diagnostic and prognostic biomarker for breast cancer

Inhibiting Pin1 has potentially striking therapeutic efficacy on breast cancer

Rational administration of Pin1 inhibitors for the breast cancer therapy

Conclusions

Conflict of interest statement

Acknowledgments

Pharmacol Res

Pharmacol Res

Pharmacol Res

Pharmacol Res

Pharmacol Res

Trends Biochem Sci

J Geriatr Oncol

Med Hypotheses

Med Hypotheses

Trends Biochem Sci

J Biol Chem

Mol Cell

Mol Cell

Ann Oncol

Cancer Epidemiol

J Biol Chem

J Proteomics

Mol Cell

Cancer Lett

Cell Signal

Neoplasia

J Biol Chem

J Biol Chem

Mol Cell

Mol Cell

Cancer Cell

Pharmacol Res

Exp Mol Pathol

Breast

Biochem Biophys Res Commun

FEBS Lett

Biochem Biophys Res Commun

Food Chem Toxicol

The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease

Nat Rev Mol Cell Biol

Peptidyl-prolyl cis-trans isomerase Pin1 in ageing, cancer and Alzheimer disease

Expert Rev Mol Med

Pin1: a new genetic link between Alzheimer's disease, cancer and aging

Curr Aging Sci

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

Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1

EMBO J

Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis

Mol Cell Biol

Pin1 contributes to cervical tumorigenesis by regulating cyclin D1 expression

Oncol Rep

Ras-induced and extracellular signal-regulated kinase 1 and 2 phosphorylation-dependent isomerization of protein tyrosine phosphatase (PTP)-PEST by PIN1 promotes FAK dephosphorylation by PTP-PEST

Mol Cell Biol

Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer

Cancer Res

The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer

Nat Cell Biol

The prolyl isomerase Pin1 interacts with a ribosomal protein S6 kinase to enhance insulin-induced AP-1 activity and cellular transformation

Carcinogenesis

Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity

Oncogene

Peptidyl-prolyl cis/trans isomerase Pin1 is critical for the regulation of PKB/Akt stability and activation phosphorylation

Oncogene

Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC

Nat Cell Biol

Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes

Proc Natl Acad Sci U S A

Pin1 modulates ERalpha levels in breast cancer through inhibition of phosphorylation-dependent ubiquitination and degradation

Oncogene

Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability

Mol Cancer

Perspective
Pin1-based diagnostic and therapeutic strategies for breast cancer☆