Capturing quantitative features of protein expression from in situ fluorescence microscopic images of cancer cell populations

We present a stochastic individual-based model for the phenotypic evolution of cancer cell populations under chemotherapy. In particular, we consider the case of combination cancer therapy whereby a chemotherapeutic agent is administered as the primary treatment and an epigenetic drug is used as an adjuvant treatment. The cell population is structured by the expression level of a gene that controls cell proliferation and chemoresistance. In order to obtain an analytical description of evolutionary dynamics, we formally derive a deterministic continuum counterpart of this discrete model, which is given by a nonlocal parabolic equation for the cell population density function. Integrating computational simulations of the individual-based model with analysis of the corresponding continuum model, we perform a complete exploration of the model parameter space. We show that harsher environmental conditions and higher probabilities of spontaneous epimutation can lead to more effective chemotherapy, and we demonstrate the existence of an inverse relationship between the efficacy of the epigenetic drug and the probability of spontaneous epimutation. Taken together, the outcomes of the model provide theoretical ground for the development of anticancer protocols that use lower concentrations of chemotherapeutic agents in combination with epigenetic drugs capable of promoting the re-expression of epigenetically regulated genes.

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p27KIP-1cyclin A and cyclin D1 protein expression in ductal carcinoma in situ of the breast: p27KIP-1correlates with hormone receptor status but not with local recurrence

Pathology International ◽

10.1111/j.1440-1827.2007.02079.x ◽

2007 ◽

Vol 57 (4) ◽

pp. 183-189 ◽

Cited By ~ 9

Author(s):

Ewan K. A. Millar ◽

Kayla Tran ◽

Penny Marr ◽

Peter H. Graham

Keyword(s):

Local Recurrence ◽

Protein Expression ◽

Ductal Carcinoma In Situ ◽

Hormone Receptor ◽

Carcinoma In Situ ◽

Ductal Carcinoma ◽

D1 Protein ◽

Hormone Receptor Status ◽

Cyclin D1 Protein

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Protein citrullination as a source of cancer neoantigens

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002549 ◽

2021 ◽

Vol 9 (6) ◽

pp. e002549

Author(s):

Hiroyuki Katayama ◽

Makoto Kobayashi ◽

Ehsan Irajizad ◽

Alejandro Sevillarno ◽

Nikul Patel ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Immune Response ◽

Protein Expression ◽

Cell Lines ◽

Cancer Cell ◽

Family Members ◽

Immunohistochemical Analysis ◽

Cancer Cell Lines ◽

Mhc Ii

BackgroundCitrulline post-translational modification of proteins is mediated by protein arginine deiminase (PADI) family members and has been associated with autoimmune diseases. The role of PADI-citrullinome in immune response in cancer has not been evaluated. We hypothesized that PADI-mediated citrullinome is a source of neoantigens in cancer that induces immune response.MethodsProtein expression of PADI family members was evaluated in 196 cancer cell lines by means of indepth proteomic profiling. Gene expression was assessed using messenger RNA data sets from The Cancer Genome Atlas. Immunohistochemical analysis of PADI2 and peptidyl-citrulline was performed using breast cancer tissue sections. Citrullinated 12–34-mer peptides in the putative Major Histocompatibility Complex-II (MHC-II) binding range were profiled in breast cancer cell lines to investigate the relationship between protein citrullination and antigen presentation. We further evaluated immunoglobulin-bound citrullinome by mass spectrometry using 156 patients with breast cancer and 113 cancer-free controls.ResultsProteomic and gene expression analyses revealed PADI2 to be highly expressed in several cancer types including breast cancer. Immunohistochemical analysis of 422 breast tumor tissues revealed increased expression of PADI2 in ER− tumors (p<0.0001); PADI2 protein expression was positively correlated (p<0.0001) with peptidyl-citrulline staining. PADI2 expression exhibited strong positive correlations with a B cell immune signature and with MHC-II-bound citrullinated peptides. Increased circulating citrullinated antigen–antibody complexes occurred among newly diagnosed breast cancer cases relative to controls (p=0.0012).ConclusionsAn immune response associated with citrullinome is a rich source of neoantigens in breast cancer with a potential for diagnostic and therapeutic applications.

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MAT2A Localization and Its Independently Prognostic Relevance in Breast Cancer Patients

International Journal of Molecular Sciences ◽

10.3390/ijms22105382 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5382

Author(s):

Pei-Yi Chu ◽

Hsing-Ju Wu ◽

Shin-Mae Wang ◽

Po-Ming Chen ◽

Feng-Yao Tang ◽

...

Keyword(s):

Breast Cancer ◽

Survival Rate ◽

Protein Expression ◽

Cancer Patients ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cell Lines ◽

Breast Cancer Patients ◽

Expression Ratio

(1) Background: methionine cycle is not only essential for cancer cell proliferation but is also critical for metabolic reprogramming, a cancer hallmark. Hepatic and extrahepatic tissues methionine adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A that catalyze the formation of S-adenosylmethionine (SAM), the principal biological methyl donor. Glycine N-methyltransferase (GNMT) further utilizes SAM for sarcosine formation, thus it regulates the ratio of SAM:S-adenosylhomocysteine (SAH). (2) Methods: by analyzing the TCGA/GTEx datasets available within GEPIA2, we discovered that breast cancer patients with higher MAT2A had worse survival rate (p = 0.0057). Protein expression pattern of MAT1AA, MAT2A and GNMT were investigated in the tissue microarray in our own cohort (n = 252) by immunohistochemistry. MAT2A C/N expression ratio and cell invasion activity were further investigated in a panel of breast cancer cell lines. (3) Results: GNMT and MAT1A were detected in the cytoplasm, whereas MAT2A showed both cytoplasmic and nuclear immunoreactivity. Neither GNMT nor MAT1A protein expression was associated with patient survival rate in our cohort. Kaplan–Meier survival curves showed that a higher cytoplasmic/nuclear (C/N) MAT2A protein expression ratio correlated with poor overall survival (5 year survival rate: 93.7% vs. 83.3%, C/N ratio ≥ 1.0 vs. C/N ratio < 1.0, log-rank p = 0.004). Accordingly, a MAT2A C/N expression ratio ≥ 1.0 was determined as an independent risk factor by Cox regression analysis (hazard ratio = 2.771, p = 0.018, n = 252). In vitro studies found that breast cancer cell lines with a higher MAT2A C/N ratio were more invasive. (4) Conclusions: the subcellular localization of MAT2A may affect its functions, and elevated MAT2A C/N ratio in breast cancer cells is associated with increased invasiveness. MAT2A C/N expression ratio determined by IHC staining could serve as a novel independent prognostic marker for breast cancer.

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The Prognostic Impact of HER2 Genetic and Protein Expression in Pancreatic Carcinoma—HER2 Protein and Gene in Pancreatic Cancer

Diagnostics ◽

10.3390/diagnostics11040653 ◽

2021 ◽

Vol 11 (4) ◽

pp. 653

Author(s):

Song-Hee Han ◽

Ki Hyun Ryu ◽

Ah-Young Kwon

Keyword(s):

Protein Expression ◽

Genetic Heterogeneity ◽

Growth Factor Receptor ◽

Ductal Adenocarcinoma ◽

Prognostic Impact ◽

Her2 Expression ◽

Her2 Protein ◽

Epidermal Growth ◽

Her2 Heterogeneity

Pancreatic ductal adenocarcinoma (PDAC) is a lethal and clinically heterogeneous disease with a limited benefit from human epidermal growth factor receptor 2 (HER2)-targeted therapy. Recently, some studies have addressed the antitumoral effect of novel anti-HER2 drugs in HER2 low-expressing tumors. However, there have been few studies on the significance of low HER2 expression and genetic heterogeneity in PDAC. Using immunohistochemistry and dual-color silver-enhanced in situ hybridization based on the Trastuzumab for a gastric cancer scoring scheme, we evaluated HER2 protein expression, gene amplification, and genetic heterogeneity in three groups (HER2-neg, HER2-low, HER2-pos) of 55 patients. Among the 55 cases, 41.8% (23/55) showed HER2 expression of any intensity. HER2 amplification independent of HER2 expression was 25.5% (14/55). Patients in both these groups had a shorter overall survival than did patients in the HER2-neg group. HER2 genetic heterogeneity was identified in 37 (70.9%) of the 55 cases, mainly in HER2-neg and HER2-low groups. HER2 genetic heterogeneity significantly correlated with worse survival in the HER2-low and HER2-neg groups of PDAC. These findings support the hypothesis that low-level HER2 expression and heterogeneity have significant clinical implications in PDAC. HER2 heterogeneity might indicate the best strategies of combination therapies to prevent the development of subdominant clones with resistance potential.

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