A Functional and Regulatory Network Associated with PIP Expression in Human Breast Cancer

Abstract

BackgroundThe PIP (prolactin-inducible protein) gene has been shown to be expressed in breast cancers, with contradictory results concerning its implication. As both the physiological role and the molecular pathways in which PIP is involved are poorly understood, we conducted combined gene expression profiling and network analysis studies on selected breast cancer cell lines presenting distinct PIP expression levels and hormonal receptor status, to explore the functional and regulatory network of PIP co-modulated genes.Principal FindingsMicroarray analysis allowed identification of genes co-modulated with PIP independently of modulations resulting from hormonal treatment or cell line heterogeneity. Relevant clusters of genes that can discriminate between [PIP+] and [PIP−] cells were identified. Functional and regulatory network analyses based on a knowledge database revealed a master network of PIP co-modulated genes, including many interconnecting oncogenes and tumor suppressor genes, half of which were detected as differentially expressed through high-precision measurements. The network identified appears associated with an inhibition of proliferation coupled with an increase of apoptosis and an enhancement of cell adhesion in breast cancer cell lines, and contains many genes with a STAT5 regulatory motif in their promoters.ConclusionsOur global exploratory approach identified biological pathways modulated along with PIP expression, providing further support for its good prognostic value of disease-free survival in breast cancer. Moreover, our data pointed to the importance of a regulatory subnetwork associated with PIP expression in which STAT5 appears as a potential transcriptional regulator.

Amplification of the prolactin receptor gene in mammary lobular neoplasia

“…GCDFP-15, also known as prolactin inducible protein (PIP), has been shown, in early in vitro studies, to be regulated by a number of hormones, including prolactin [42]. It is thought that this regulation is mediated via STAT5a [54,55]. In our series, there was a higher expression rate of GCDFP-15 in lobular compared to ductal in situ lesions (75% vs. 55%), although our numbers did not reach statistical significance.…”

Additive effect of the AZGP1, PIP, S100A8 and UBE2C molecular biomarkers improves outcome prediction in breast carcinoma

“…Prolactin‐inducible protein (PIP) is a secreted monomer glycoprotein that is expressed in exocrine glands, gross cystic disease and breast cancers exhibiting apocrine features . T47D, where the PIP gene is duplicated as a palindrome of the 7q34–q35 genomic region, and recently VHB1 breast cell lines are among the only cells, which show the suppression of cell proliferation and migration as well as the induction of apoptosis in androgen‐stimulated PIP‐expressing cells . Androgens also stimulate the release of AZGP1 and apoD in T47D cells.…”

Pathogenesis of Keratoconus: The intriguing therapeutic potential of Prolactin-inducible protein

“…On the subcellular level, the signal transducer and activator of transcription 5 (Stat5) and Runx2 works through AR to regulate PIP expression (Debily et al, 2009; Haagensen et al, 1990; Naderi et al, 2012). However, further studies are required to understand the molecular mechanisms of PIP action and its translational implications in various tissues, specifically in breast tumours.…”