Prognostic Role of Prolactin-Induced Protein (PIP) in Breast Cancer

Abstract

Prolactin-inducible protein (PIP), also referred to as gross cystic disease fluid protein 15 (GCDFP-15), has been a trending topic in recent years due to its potential role as a specific marker in breast cancer. PIP binds to aquaporin-5 (AQP5), CD4, actin, fibrinogen, β-tubulin, serum albumin, hydroxyapatite, zinc α2-glycoprotein, and the Fc fragment of IgGs, and the expression of PIP has been demonstrated to be modulated by various cytokines, including IL4/13, IL1, and IL6. PIP gene expression has been extensively studied due to its captivating nature. It is influenced by various factors, with androgens, progesterone, glucocorticosteroids, prolactin, and growth hormone enhancing its expression while estrogens suppress it. The regulatory mechanisms involve important proteins such as STAT5A, STAT5B, Runx2, and androgen receptor, which collaborate to enhance PIP gene transcription and protein production. The expression level of PIP in breast cancer is dependent on the tumor stage and subtype. Higher expression is observed in early-stage tumors of the luminal A subtype, while lower expression is associated with luminal B, basal-like, and triple-negative subtypes, which have a poorer prognosis. PIP expression is also correlated with apocrine differentiation, hormone receptor positivity, and longer metastasis-free survival. PIP plays a role in supporting the immune system's antitumor response during the early stages of breast cancer development. However, as cancer progresses, the protective role of PIP may become less effective or diminished. In this work, we summarized the clinical significance of the PIP molecule in breast cancer and its potential role as a new candidate for cell-based therapies.

Keywords: breast cancer; gross cystic disease fluid protein 15 (GCDFP-15); prolactin-inducible protein (PIP).

Figure 1

Crystal structure of the complex formed between zinc 2-glycoprotein (ZAG) and prolactin-inducible protein (PIP) [11].

Figure 2

PIP expression overview in tissues of the human body, visualization shows RNA-seq data generated by The Cancer Genome Atlas (TCGA) (image credit: Human Protein Atlas www.proteinatlas.org. Image available at the following URL: https://v21.proteinatlas.org/ENSG00000159763-PIP/tissue, accessed on 9 July 2023).

Figure 3

The antigen location on the target protein(s) and the features of the target protein. At the top, the position of the antigen (identified by the corresponding HPA identifier) is shown as a green bar. Below the antigens, the maximum percent sequence identity of the protein to all other proteins from other human genes is displayed, using a sliding window of 10 aa residues (HsID 10) or 50 aa residues (HsID 50). The region with the lowest possible identity is always selected for antigen design, with a maximum identity of 60% allowed for designing a single-target antigen. The curve in blue displays the predicted antigenicity, i.e., the tendency for different regions of the protein to generate an immune response, with peak regions being predicted to be more antigenic. The curve shows average values based on a sliding window approach using an in-house propensity scale. If a signal peptide predicted by a majority of the signal peptide predictors SPOCTOPUS, SignalP 4.0, and Phobius (turquoise) is predicted by MDM, it is displayed. Low-complexity regions are shown in yellow and InterPro regions in green. Common (purple) and unique (grey) regions between different splice variants of the gene are also displayed, and at the bottom of the protein view is the protein scale. (Image credit: Human Protein Atlas www.proteinatlas.org. Image available at the following URL: https://v21.proteinatlas.org/ENSG00000159763-PIP#gene_information, accessed on 9 July 2023).

Figure 4

One of the regulatory mechanisms of PIP. The mechanism involves several steps as follows: (1) Prolactin (PRL) binding to prolactin receptor (PRLR); (2) phosphorylation in STAT5; (3) dimerization of STAT5; (4) entering the nucleus by STAT5; (5) binding to the STAT5-responsive element (STAT5 RE) by STAT5, binding by the androgen receptor (AR) to androgen-responsive elements (AREs), enhancing PIP expression of PIP gene.

Figure 5

One of the regulatory mechanisms of PIP. The mechanism involves several steps as follows: (1) Binding 5α-dihydrotestosterone (DHT) to the androgen receptor (AR) inducing dimerization of the AR; (2) AR entering nucleus facilitated by PIP; (3) binding to enhancer element of the PIP promoter by androgen receptor and Runx2 increasing expression of the PIP gene. ** Stimulation of androgen-dependent genes by PIP.

Figure 6

One of the regulatory mechanisms of PIP: PIP possesses aspartic-type protease activity, targeting fibronectin and activating β1-integrin. This triggers a cascade involving ILK1, ErbB2, ERK, and Akt signaling pathways. ERK and Akt phosphorylate RSK and MSK kinases, leading to CREB1 activation and increased PIP gene transcription. Positive feedback loops involve PIP degradation of fibronectin, CREB1 transcriptional regulation, and AR-mediated induction of ErbB2.