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The Phosphorylation Status of PIP5K1C at Serine 448 Can Be Predictive for Invasive Ductal Carcinoma of the Breast

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The Phosphorylation Status of PIP5K1C at Serine 448 Can Be Predictive for Invasive Ductal Carcinoma of the Breast www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 91), pp: 36358-36370 Research Paper The phosphorylation status of PIP5K1C at serine 448 can be predictive for invasive ductal carcinoma of the breast Nisha Durand1, Sahra Borges1, Tavia Hall1, Ligia Bastea1, Heike Döppler1, Brandy H. Edenfield1, E. Aubrey Thompson1, Xochiquetzal Geiger2 and Peter Storz1 1Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL 32224, USA 2Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL 32224, USA Correspondence to: Peter Storz, email: [email protected] Keywords: PIP5K1C; breast cancer; invasive phenotype; phosphorylation Received: June 09, 2018 Accepted: October 31, 2018 Published: November 20, 2018 Copyright: Durand et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Phosphatidylinositol-4-phosphate 5-kinase type-1C (PIP5K1C) is a lipid kinase that regulates focal adhesion dynamics and cell attachment through site-specific formation of phosphatidylinositol-4,5-bisphosphate (PI4,5P2). By comparing normal breast tissue to carcinoma in situ and invasive ductal carcinoma subtypes, we here show that the phosphorylation status of PIP5K1C at serine residue 448 (S448) can be predictive for breast cancer progression to an aggressive phenotype, while PIP5K1C expression levels are not indicative for this event. PIP5K1C phosphorylation at S448 is downregulated in invasive ductal carcinoma, and similarly, the expression levels of PKD1, the kinase that phosphorylates PIP5K1C at this site, are decreased. Overall, since PKD1 is a negative regulator of cell migration and invasion in breast cancer, the phosphorylation status of this residue may serve as an indicator of aggressiveness of breast tumors. INTRODUCTION these gene clusters suggests altered phosphoinositide lipid signaling and lipid-regulated trafficking in these cancers. The family of phosphatidylinositol-4-phosphate While little is known on the cellular functions of 5-kinase type-1 (PIP5K1) lipid kinases consists of three the two other PIP5K1 enzymes, PIP5K1C (PIP5K1γ) has isoforms, PIP5K1A, PIP5K1B and PIP5K1C, each of been shown to be a major regulator of focal adhesion (FA) which exists in multiple alternatively spliced variants. dynamics [4]. Depletion of PIP5K1C leads to cytoskeletal changes and severe attachment defects in cells [5]. Altered PIP5K1 enzymes regulate formation of PI4,5P2 at distinct locations within cells, using phosphatidylinositol-4- FA dynamics due to decrease in PIP5K1C activity or phosphate (PI4P) as a substrate [1]. However, little expression has been linked to increased cell migration and is known with respect to the roles of these enzymes in invasion [6, 7]. PIP5K1C localization to FA is negatively- cancer development or progression. In breast cancer it regulated by p35/Cdk5-mediated phosphorylation at was shown that PIP5K1A gene copy numbers, together S650 [8]; and PIP5K1C degradation is regulated by with other genes such as AKT3, PI4KB and PI3KC2B in phosphorylation through p70S6K1 at threonine 553 and an amplification stretch in chromosome 1q, are increased serine 555 [7], while its lipid kinase activity is inhibited in a large percentage of tumors [2]. In glioblastoma after phosphorylation through protein kinase D (PKD) at multiforme, copy number amplifications in chromosome serine 448 [9]. 19 have been described leading to increased expression of Members of the PKD family of serine/threonine PIP5K1C, AKT2 and PIK3R2 [2]. In addition, differential kinases control multiple functions within cells by expression of PIP5K1B, PIP5K1C and PIP4K2B has been phosphorylating a broad spectrum of targets [10]. In breast described for lung adenocarcinoma [3]. The regulation of cancer all three isoforms (PKD1, PKD2 and PKD3) have www.oncotarget.com 36358 Oncotarget been implicated in regulating cancer cell survival and normal breast tissue, ductal carcinoma in situ (DCIS), 3 proliferation during tumor formation [11–14]. However, groups of invasive ductal carcinomas (ER positive; HER2 with respect to cell migration and invasiveness, it was positive; or TN) as well as invasive lobular carcinoma shown that PKD1 blocks these events through multiple (ILC) using IHC. Our results suggest that levels of total mechanisms. These include PKD1-induced changes in the PIP5K1C are not indicative for BC progression (Figure stability of cell-cell contacts [15–17], in focal adhesion 1C). Eventually, we determined if PIP5K1C gene dynamics [9, 17], in actin reorganization dynamics [18– expression levels can be linked to distant metastases free 20] and in filopodia formation and stabilization [21]. survival (DMFS) in patients. Therefore, we analyzed a set Additionally, PKD1 has been shown to block epithelial- of 1746 patient samples for which gene expression data to-mesenchymal transition (EMT) [22–24], and to mediate was available. Samples were split by median and DMFS changes in the expression of matrix metalloproteinases plotted over time. The analysis was performed using the (MMPs) [25]. Consequently, in breast cancer, the Kaplan-Meier Plotter (http://kmplot.com/analysis/index. transition from a less aggressive to a metastatic phenotype php?p=service&cancer=breast), previously described [27]. is characterized by PRKD1 (PKD1) gene promoter We did not detect a statistical difference between patients methylation and downregulation of PKD1 expression with high or low expression of PIP5K1C with respect to [14, 26]. DMFS (Figure 1D). We here investigated if expression of PIP5K1C or Overall, our data lead to the conclusion that its phosphorylation status at serine 448 can be indicative PIP5K1C expression levels are not significantly changed for invasive breast cancers. Our data suggest that PKD1 in different subtypes of breast cancer and also are not expression levels in tumors correlate with PIP5K1C indicative for patient survival. phosphorylation at serine 448, and that the PIP5K1C phosphorylation at this residue may be a predictive marker Phosphorylation of PIP5K1C at S448 is for progression to an aggressive phenotype. decreased in invasive ductal carcinoma of the breast RESULTS We previously have shown that PIP5K1C lipid kinase The expression level of PIP5K1C is not activity is inhibited after phosphorylation at serine 448, predictive for breast cancer survival or subtype and have generated a phospho-specific antibody (pS448- PIP5K1C) for this site [9]. Therefore, we investigated if Alterations in PIP5K1C expression or the phosphorylation status of PIP5K1C at S448 is altered activity have been linked to increased cell with increasing invasiveness of breast cancers. First, we migration and invasion [6, 7]. We used cBioPortal confirmed specificity of our pS448-PIP5K1C antibody by (http://www.cbioportal.org/public-portal/index.do) to using phosphorylated blocking peptides on normal breast analyze three different available datasets, including tissue (Figure 2A). Using this antibody we determined the 2509 breast cancer (BC) samples, 1105 invasive breast phosphorylation status in a set of n = 75 samples of IDC carcinoma (IBC, BIC) samples, or 216 metastatic breast or normal breast tissue, and found a significant decrease in cancers (MBC) for gene alterations such as amplification, PIP5K1C phosphorylation at S448 in IDC (Figure 2B). To deletion or mutational events in PIP5K1A, PIP5K1B and further dissect this into IDC subgroups, we then analyzed our PIP5K1C genes. While we detected gene amplification of progression tissue microarrays (TMAs) including normal PIP5K1A, which is consistent with previously published breast tissue, ductal carcinoma in situ (DCIS), 3 groups of data [2], in all three datasets, the alteration frequency for invasive ductal carcinomas (ER positive; HER2 positive; PIP5K1B and PIP5K1C was very low (Figure 1A). or TN) as well as invasive lobular carcinoma (ILC) for this However, the PIP5K1C gene amplification phosphorylation. Quantification of the pS448-PIP5K1C frequency slightly increased when comparing the BC to phosphorylation status after immunohistochemical (DAB MBC datasets which prompted us to further determine if staining) analysis indicated a statistically significant decrease the expression levels of PIP5K1C can be predictive for in different subtypes of invasive ductal carcinoma of the breast cancer subtypes or aggressiveness. Therefore, we breast, but not in ILC (representative pictures in Figure 2C, first investigated a panel of 51 breast cancer cell lines quantification in Figure 2D). using GOBO from Lund University (http://co.bmc.lu.se/ gobo/) (Figure 1B). Cells were grouped either into basal or Phosphorylation of PIP5K1C at S448 in breast luminal subtypes (left side) or grouped into TN, HER2+ or cancer cells is mainly mediated by PKD1 HR+ subtypes (right side). We did not observe a statistical difference in PIP5K1C expression within these groups. We previously have shown that in Hek293T cells the Next, we tested if PIP5K1C protein expression is phosphorylation of PIP5K1C at S448 can be mediated by altered during progression of breast cancer. Therefore, we PKD1 and PKD2 enzymes [9]. In order to determine which analyzed progression tissue microarrays (TMAs) including of these two PKD isoforms are responsible for PIP5K1C www.oncotarget.com 36359 Oncotarget phosphorylation in breast cancer cells,
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