PIN1 in breast development and cancer: a clinical perspective

Abstract

Mammary gland development, various stages of mammary tumorigenesis and breast cancer progression have the peptidyl-prolyl cis/trans isomerase PIN1 at their centerpiece, in virtue of the ability of this unique enzyme to fine-tune the dynamic crosstalk between multiple molecular pathways. PIN1 exerts its action by inducing conformational and functional changes on key cellular proteins, following proline-directed phosphorylation. Through this post-phosphorylation signal transduction mechanism, PIN1 controls the extent and direction of the cellular response to a variety of inputs, in physiology and disease. This review discusses PIN1's roles in normal mammary development and cancerous progression, as well as the clinical impact of targeting this enzyme in breast cancer patients.

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

“…The N-terminal (WW domain contained) of Pin1 is critical for the recognition of pSer/Thr-Pro peptides while the C-terminal (PPIase domain contained) plays the catalytic role of isomerization. Since a majority of phosphorylating events during cellular signaling locate on serine or threonine residues, it is relatively comprehensible that pSer/Thr-Pro isomerization by Pin1 may play a role in multiple physiological or pathological processes [309]. For example, increased expression of Pin1 has been detected in lung, prostate and breast cancer cells, which also acts as an unfavorable indicator of clinical prognosis.…”

Peptidyl‐prolyl cis/trans isomerase Pin1 regulates withaferin A‐mediated cell cycle arrest in human breast cancer cells

“…The present study shows downregulation of Pin1 by WA treatment in breast cancer cells. Overexpression of Pin1 protein in breast cancer is associated with poor clinical outcome . Pin1 plays an important role in normal mammary development as well as in breast cancer progression by regulating stability or activity of numerous proteins .…”

“…Overexpression of Pin1 protein in breast cancer is associated with poor clinical outcome . Pin1 plays an important role in normal mammary development as well as in breast cancer progression by regulating stability or activity of numerous proteins . Some of the targets of Pin1 (eg, estrogen receptor‐α, STAT3, NF‐κB, Notch‐1) are also downregulated by WA treatment.…”

“…We showed previously that breast cancer prevention by WA in MMTV‐ neu mice was associated with a decrease in protein levels of peptidyl‐prolyl cis/trans isomerase (Pin1) through unbiased proteomics . The Pin1 protein, which plays an important role in mammary gland development as well as in various steps of breast cancer progression, catalyzes cis/trans isomerization of phospho‐Ser/Thr‐Pro motifs in many proteins . Because Pin1 controls isomerization of numerous cancer‐relevant proteins, it is considered a valid therapeutic target .…”

Structure and function of the human parvulins Pin1 and Par14/17

“…Subsequent reactions are often the initiation or prevention of PTM processes such as ubiquitination (Siepe and Jentsch, 2009) or conformer-specific protein-protein interactions . Depending on this outcome Pin1 could enhance (Lee et al, 2009b) or weaken Eckerdt et al, 2005;Luo et al, 2010;Khanal et al, 2012) protein stability and influence protein turn-over; it can drive protein cascades in signaling events (Keune et al, 2013;Toko et al, 2013;Antonelli et al, 2014;So and Oh, 2015;Rustighi et al, 2017) or regulate metabolic processes such as the insulin dependent glucose uptake (Nakatsu et al, 2009).…”