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.

Figure 1

PIN1 regulates several cellular processes in breast cancer depending on the substrates. Schematic representation of breast cancer-specific PIN1 substrates and the involved biological processes. Products of oncogenes and tumor suppressors are indicated in red and green boxes, respectively. Arrows and blunted lines indicate a positive or negative action of PIN1, respectively, eliciting a particular cellular outcome, as indicated in the gray boxes

Figure 2

PIN1 is required for both normal mammary gland morphogenesis and breast cancer progression through regulation of multiple cellular processes. Top: the phases of normal breast development and tumor progression in which a role of PIN1 has been demonstrated are schematically represented from left to right. Specific conditions, where coordination of different pathways requires PIN1 activity, are indicated in red. Below, specific cellular processes occurring during the abovementioned phases and the involved PIN1 substrates are indicated. Oncogenes and tumor suppressors are indicated in red and green boxes, respectively. In gray boxes putative PIN1 substrates involved in human breast morphogenesis. Bottom: The levels/activity of PIN1 that increase from normal mammary gland to tumors progressing to high-grade cancers are represented by a red wedge. Asterisks indicate cellular processes regulated by PIN1 in contexts different fom breast tissue. SC, stem cells

Figure 3

PIN1 is not a frequently altered gene in human cancers. Analysis of mutations (Mutation data) and copy number (CNA data) of human PIN1 was performed across all human tumor types in the TCGA cancer panel (obtained from cbioportal cross-cancer mutations). In the histogram only those tumors are indicated, where alterations of human PIN1 were found: alteration frequencies along with copy number variation data are provided. Breast cancers display amplifications of PIN1 in only 1.5% of the analyzed cases

Figure 4

Regulation of PIN1 expression in breast cancer. Upper part: Schematic representation of the human PIN1 gene, encompassing the promoter sequence, the 5' and 3' untranslated regions (UTRs), and exons 1–4 (Ex). Known cis-elements and the upstream signals and trans-acting factors are indicated; CSL Notch-responsive element. Middle part: Scheme of the mature PIN1 mRNA targeted by mir-200. Lower part: Schematic of the PIN1 protein structure with the sites of regulatory post-translational modifications and the responsible enzymes. The type IV WW domain, the linker region in between, and the PPIase domain are indicated. The nuclear localization signal is depicted as a small gray box within the PPIase domain. Modified aminoacid residues of PIN1 are indicated with a circle, enzymes acting on the specific residue with activating or repressing function on PIN1 are indicated in black boxed or in gray letters, respectively