Table 2.
Summary of reported correlations/associations of PDIA3 and other classical PDI family members with human breast cancer cell functions and/or clinical samples
| PDI Family Member | Correlation/Functionality in Human Breast Cancer Cells or Tumors |
Reference | ||
|---|---|---|---|---|
| Biological Sample | Major Expt. Methods | Results | ||
| PDIA1/P4HB | IDC and adjacent normal breast tissue | Proteomics | PDI among a set of proteins increased in IDC sample | (111) |
| Tissue samples of 9 breast cancers from male patients | 2D IEF/NEPHGE and proteomics; immunoblot, IHC | PDIA1 among proteins increased in tumor vs. normal tissue | (112) | |
| Tumor (n = 69) or normal (n = 28) breast interstitial fluid; TMA | Proteomics; IHC; TMA | PDIA1 among the consistently greater than twofold upregulated proteins in tumor interstitial fluid; confirmed on TMA | (113) | |
| Samples of 11 primary breast cancers and matched axillary lymph node metastases | 2-D-gel electrophoresis; Proteomics; IHC | PDI among the proteins consistently upregulated in lymph node metastasis vs. primary tumor | (114) | |
| MCF10A, MCF7, and MDA-MB-231 cells | Q3Rut, PACMA-31, and 16F16 inhibitors; assays of cell proliferation, attachment, migration, and transendothelial invasion | Cell-specific effects on proliferation, adhesion, migration, adhesion to endothelial monolayers, invasion and collagen gel contraction; alterations to free thiols of integrins; cell-surface PDIA1 detected | (115) | |
| MCF-7 and MDA-MB-231 cells | Bepristat 2a inhibition | Reduced cell adhesion to ECM proteins and to human microvascular endothelial cells; reduced transendothelial migration | (116) | |
| MCF-7 and MDA-MB-231 cells; breast cancer patient samples | siRNA-silencing | Cell-type specific effects on ROS, GSH, and ATP levels; reduced cell-surface HLA-G; correlation of low PDIA3 and high HLA-G with increased OS of patients with stage 2 breast cancer | (117) | |
| Plasma of 51 nonmetastatic patients with breast cancer receiving neo-adjuvant chemotherapy | Plasma proteomics; clinical correlations | Elevated P4HB correlated with patients with pathological incomplete response to therapy, also with tumor stage; high expression correlated with decreased disease-free survival time | (118) | |
| MCF-7 and MDA-MB-231 cells | siRNA-silencing, RNASeq | Identification of up/down regulated genes after silencing, comparison of gene expression changes after IFNγ or etoposide treatments; relevance of pro-oncogenic gene sets and ER-status to OS correlations. | (119) | |
| T47D and MDA-MB-468 cells | Affinity purification of endogenous biotinylated proteins and proteomics | Identification of PDIA1 as a binding partner of a disulfide bond disrupting agent, an agent known to downregulate HER2 family proteins and kill breast cancer cells. | (120) | |
| MCF-7 and MDA-MB-231 cells | Proteomic ID of PDI family members in cancer cell lines; novel PDIA1/ PDIA3 inhibitors | Antiproliferative activity of inhibitors; reduced cell adhesion to collagen I | (121) | |
| PDIA3 | MCF-7, T47D, MDA-MB-231, and MCF-12A cells | siRNA-silencing; cell proliferation and cell cycle analysis | Reduced proliferation of T47D cells upon PDIA3 silencing; cell-cycle arrest in G1 phase; minor increase in apoptosis | (122) |
| Samples of 1 DCIS, 2 IDC and matched normal breast tissue | Mass spectrometry, proteomics, immunoblot | PDIA3 included in a signature of significantly upregulated proteins in DCIS and IDC relative to normal breast tissue | (123) | |
| MDA-MB-231 cells and BO2 bone metastatic subline | Proteomics; transcriptomics; primary and bone tumor analysis in nude mice; siRNA or shRNA silencing | PDIA3 included in a suite of proteins upregulated in BO2 cells and also predicted to network with multiple up- or downregulated proteins and cell adhesion proteins. Silencing of PDIA3 in BO2 cells reduced bone metastatic growth in vivo | (124) | |
| MDA-MB-468 cells | siRNA silencing; EGF receptor location and functional parameters | Silencing of PDIA3 led to reduced EGF receptor phosphorylation and internalization | (125) | |
| Samples of 45 primary IDC and 9 normal contra-lateral samples | RT-PCR for PDIA3 and PDIA6 | PDIA3 expression significantly increased in carcinomas, in tumors with lymph node metastasis and with grade III | (126) | |
| Five paired samples of IDC and nontumor breast tissue. No neoadjuvant therapy | 2-D-polyacrylamide gel electrophoresis; mass spectrometry | 4.8-fold increase in PDIA3 protein in IDC samples (among top 10 elevated proteins) | (127) | |
| MDA-MB-231 cells | shRNA silencing; cellular assays | PDIA3 silencing led to protection against etoposide-induced apoptosis, PERK activation, G2 cell cycle arrest and reduced cell proliferation | (128) | |
| 3 IDC and 3 invasive lobular carcinoma tissue specimens | 2-D-polyacrylamide gel electrophoresis; mass spectrometry | PDIA3 upregulated in IDC relative to invasive lobular carcinoma | (129) | |
| SUM159PT and MCF10DCIS.com cells | shRNA silencing of PDIA1, PDIA3; Mammosphere anchorage-independent growth | Increased expression of PDIA3 and ECM genes in mammospheres vs. 2-D culture; mammosphere volume growth decreased by PDIA1 or PDIA3 silencing | (130) | |
| MCF-7, MDA-MB-231, and HCC1937 cells | PACMA-31 and 16F16 inhibitors; CM from WT- and pdia3-null mouse embryo fibroblasts (MEF); cell adhesion and migration assays | 16F16 more active than PACMA-31 in decreasing cell attachment, spreading, F-actin and focal adhesion organization and cell migration; reduced cell-adhesive activity of ECM of HCC1937 cells treated with 16F16; decreased activity of CM of pdia3-null MEF to support breast cancer cell spreading and F-actin or migration | (131) | |
| Triple-negative breast cancer samples and public databases | Mouse model, cellular methods; analysis of single-cell transcriptomes of breast cancer and infiltrating immune cells | PDIA3 present on the surface of tumor-associated macrophages from TNBC; High expression of PDIA3 in macrophages of M2 phenotypes correlated with poor prognosis and immune suppression markers | (132) | |
| MDA-MB-231 cells | Inhibitor dihydrotanshinone I; Affinity chromatography and mass spectrometry; biochemical and cell-based assays | Dihydrotanshinone I identified as a new binding partner and inhibitor of PDIA3 redox activity; in cells, reduced viability, decreased PDIA3 protein, also increased ER stress and apoptosis | (133) | |
| MDA-MB-231 cells | 16F16 inhibition; TMT-proteomics on CM; in. silico data analysis | 16F16 treatment resulted in 80 proteins of reduced abundance in CM, including many networked ECM proteins; high expression of these correlated with reduced DMFS of basal-type patients with breast cancer | (134) | |
| PDIA6 | MCF-7 and MDA-MB-436 cells; breast cancer TMA | PDIA6 over-expression; phosphorylation status of ErbB2; activity state of ErbB2 pathway proteins; TMA | Increased migration or invasion and increased active ErbB2 in PDIA6-over-expressing cells; elevated PDIA6 in invasive ductal carcinomas (IDC) | (135) |
| Samples of 45 primary IDC and 9 normal contra-lateral samples | RT-PCR for PDIA3 and PDIA6 | PDIA6 transcript significantly elevated in subgroups with lymph node metastasis and significantly reduced with hormone-receptor negative status | (126) | |
| Five paired samples of IDC and nontumor breast tissue. No neoadjuvant therapy | 2-D-polyacrylamide gel electrophoresis; mass spectrometry | 5.2-fold increase in PDIA6 protein in IDC samples (among top 10 elevated proteins) | (127) | |
| 3 IDC and 3 invasive lobular carcinoma tissue specimens | 2-D-polyacrylamide gel electrophoresis; mass spectrometry | PDIA6 upregulated in IDC relative to invasive lobular carcinoma | (129) | |
| BT20, T47D, and MDA-MB-231 cells | Flow cytometry, immunoblotting | PDIA6 detected on the surface of breast cancer cell lines and in cell lysates | (136) | |
| HCC70 (triple-negative) and SKBR3 (HER2-positive) cells; breast cancer patients’ sera | siRNA screen for decreased breast cancer cell survival and increased apoptosis; mouse models; auto-antibody detection in patient sera | PDIA6 silencing decreased cell survival and increased apoptosis; PDIA6 vaccination of mouse model decreased tumor growth by 43%; autoantibodies to PDIA6 elevated in sera from DCIS and invasive patients with breast cancer compared with controls, also in fibroadenoma condition | (137) | |
| MCF-7, T47D, MDA-MB-231 cells | Tamoxifen treatment of cells; isolation of aggresomes; mass spectrometry | Proteins associated with unfolded protein response, including PDIA6, incorporated into aggresomes in antiestrogen sensitive, but not antiestrogen-resistant cells | (138) | |
Samples from female patients unless otherwise stated. Based on publications listed in PubMed; breast cancer literature not identified for PDIA2, PDIA4, PDIA5, or PDIA7. ATP, adenosine 5′-triphosphate; CM, conditioned medium; DCIS, ductal carcinoma in situ; DMFS, distant metastasis-free survival; ECM, extracellular matrix; EGF, epidermal growth factor; GSH, glutathione; IDC, invasive ductal carcinoma; IHC, immunohistochemistry; OS, overall survival; PERK, protein kinase RNA-like endoplasmic reticulum kinase; ROS, reactive oxygen species; RT-PCR, real-time polymerase chain reaction; TMA, tissue microarray; 2-D, two-dimensional.