Prolactin-Induced Protein (PIP) Regulates Proliferation of Luminal A Type Breast Cancer Cells in an Estrogen-Independent Manner

Abstract

Prolactin-induced Protein (PIP), an aspartyl protease unessential for normal mammalian cell function, is required for the proliferation and invasion of some breast cancer (BCa) cell types. Because PIP expression is particularly high in the Luminal A BCa subtype, we investigated the roles of PIP in the related T47D BCa cell line. Nucleic acid and antibody arrays were employed to screen effects of PIP silencing on global gene expression and activation of receptor tyrosine kinases (RTKs), respectively. Expression of PIP-stimulated genes, as defined in the T47D cell culture model, was well correlated with the expression of PIP itself across a cohort of 557 mRNA profiles of diverse BCa tumors, and bioinformatics analysis revealed cJUN and cMYC as major nodes in the PIP-dependent gene network. Among 71 RTKs tested, PIP silencing resulted in decreased phosphorylation of focal adhesion kinase (FAK), ephrin B3 (EphB3), FYN, and hemopoietic cell kinase (HCK). Ablation of PIP also abrogated serum-induced activation of the downstream serine/threonine kinases AKT, ERK1/2, and JNK1. Consistent with these results, PIP-depleted cells exhibited defects in adhesion to fibronectin, cytoskeletal stress fiber assembly and protein secretion. In addition, PIP silencing abrogated the mitogenic response of T47D BCa cells to estradiol (E2). The dependence of BCa cell proliferation was unrelated, however, to estrogen signaling because: 1) PIP silencing did not affect the transcriptional response of estrogen target genes to hormone treatment, and 2) PIP was required for the proliferation of tamoxifen-resistant BCa cells. Pharmacological inhibition of PIP may therefore serve the bases for both augmentation of existing therapies for hormone-dependent tumors and the development of novel therapeutic approaches for hormone-resistant BCa.

Combined Label-Free Quantitative Proteomics and microRNA Expression Analysis of Breast Cancer Unravel Molecular Differences with Clinical Implications

“…Some of these proteins with higher expression in TNBC samples have been previously described as overexpressed in these tumors, such as PHGDH (25), LDHB (26), S100A8, S100A9 (27), and GRP78 (28), whereas AGR2, AGR3 (29), PIP (30), and GPD1 (31), have been shown to be upregulated in ER þ breast cancer tumors in concordance with our data. These results are strained by sample size.…”

Histological hallmarks and role of Slug/ PIP axis in pulmonary hypertension secondary to pulmonary fibrosis

“…Our analysis revealed upregulation of 59 transcriptional targets of Slug in PF‐PH versus PF patients (Fig A–C). Among these genes, we identified PIP, an extracellular matrix protein known to induce cancer cell proliferation (Naderi & Meyer, ; Baniwal et al , ), and confirmed its upregulation in our PF‐PH patients (Fig D–F). The fact that we were able to validate PIP upregulation in our own cohort further strengthens the implication of PIP in PF‐PH patients.…”

“…In turn, fibronectin fragments induce cell proliferation (Naderi & Meyer, ). In another study, Baniwal et al () demonstrated that PIP inhibition decreases cell proliferation and migration through the focal adhesion kinase, which is known to be increased in the remodeled vessels of PF patients (Lagares et al , ), and promotes pulmonary artery SMC migration and proliferation in PAH (Paulin et al , ). These evidence highlight the role of PIP in cell proliferation through various mechanisms, all of which could potentially be relevant in PF‐PH pathology and should be investigated in future studies.…”

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

“…They observed that PIP silencing by siRNA, inhibited the proliferation of the tamoxifen-resistant T47D breast cancer cells (Baniwal et al, 2013). Furthermore, treatment of human breast cancer cell lines with exogenous recombinant PIP enhanced their proliferation, whereas PIP silencing in ER+ and ER-breast cancer cell lines inhibited cell proliferation and invasion through the ECM (Naderi and Meyer, 2012).…”