58 research outputs found
IKKΞ± contributes to UVB-induced VEGF expression by regulating AP-1 transactivation
Exposure to ultraviolet B (UVB) irradiation from sunlight induces the upregulation of VEGF, a potent angiogenic factor that is critical for mediating angiogenesis-associated photodamage. However, the molecular mechanisms related to UVB-induced VEGF expression have not been fully defined. Here, we demonstrate that one of the catalytic subunits of the IΞΊB kinase complex (IKK), IKKΞ±, plays a critical role in mediating UVB-induced VEGF expression in mouse embryonic fibroblasts (MEFs), which requires IKKΞ± kinase activity but is independent of IKKΞ², IKKΞ³ and the transactivation of NF-ΞΊB. We further show that the transcriptional factor AP-1 functions as the downstream target of IKKΞ± that is responsible for VEGF induction under UVB exposure. Both the accumulation of AP-1 component, c-Fos and the transactivation of AP-1 by UVB require the activated IKKΞ± located within the nucleus. Moreover, nuclear IKKΞ± can associate with c-Fos and recruit to the vegf promoter regions containing AP-1-responsive element and then trigger phosphorylation of the promoter-bound histone H3. Thus, our results have revealed a novel independent role for IKKΞ± in controlling VEGF expression during the cellular UVB response by regulating the induction of the AP-1 component and phosphorylating histone H3 to facilitate AP-1 transactivation. Targeting IKKΞ± shows promise for the prevention of UVB-induced angiogenesis and the associated photodamage
T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers
Introduction: Lymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor.
Methods: Affymetrix HG-U133A microarray data of 1,781 primary breast cancer samples from 12 datasets were included. The correlation of immune system-related metagenes with different immune cells, clinical parameters, and survival was analyzed.
Results: A large cluster of nearly 600 genes with functions in immune cells was consistently obtained in all datasets. Seven robust metagenes from this cluster can act as surrogate markers for the amount of different immune cell types in the breast cancer sample. An IgG metagene as a marker for B cells had no significant prognostic value. In contrast, a strong positive prognostic value for the T-cell surrogate marker (lymphocyte-specific kinase (LCK) metagene) was observed among all estrogen receptor (ER)-negative tumors and those ER-positive tumors with a HER2 overexpression. Moreover ER-negative tumors with high expression of both IgG and LCK metagenes seem to respond better to neoadjuvant chemotherapy.
Conclusions: Precise definitions of the specific subtypes of immune cells in the tumor can be accomplished from microarray data. These surrogate markers define subgroups of tumors with different prognosis. Importantly, all known prognostic gene signatures uniformly assign poor prognosis to all ER-negative tumors. In contrast, the LCK metagene actually separates the ER-negative group into better or worse prognosis
Prognostic significance of tumour infiltrating B-Lymphocytes in breast ductal carcinoma in situ
Aims: Tumourβinfiltrating lymphocytes (TILs) are an important component of the immune response to cancer and have a prognostic value in breast cancer. Although several studies have investigated the role of T lymphocytes in breast cancer, the role of B lymphocytes (TILβBs) in ductal carcinoma in situ (DCIS) remains uncertain. This study aimed to assess the role of TILβBs in DCIS.Methods and results: Eighty DCIS cases (36 pure DCIS and 44 mixed with invasive cancer) were stained immunohistochemically for B lineage markers CD19, CD20 and the plasma cell marker CD138. TILβBs density and localization were assessed, including relation to the inβsitu and invasive components. An association with clinicopathological data and patient outcome was performed. Pure DCIS showed a higher number of TILβBs and lymphoid aggregates than DCIS associated with invasion. In pure DCIS, a higher number of periβ and paratumoral TILβBs was associated significantly with large tumour size (P = 0.016), hormone receptor (ER/PR) negative (P = 0.008) and HER2+ status (P = 0.010). In tumours with mixed DCIS and invasive components, cases with highβdensity B lymphocytes, irrespective of their location or topographic distribution, were associated significantly with variables of poor prognosis, including larger size, high grade, lymphovascular invasion, lymph node metastases, ER/PRβnegative and HER2+ status. Outcome analysis showed that pure DCIS associated with higher numbers of B lymphocytes had shorter recurrenceβfree interval (P = 0.04); however, the association was not significant with the CD138+ plasma cell count (P = 0.07).Conclusion: Assessment of TILβB cells based on location and topographic distribution can provide prognostic information. Validation in a larger cohort is warranted
The Tumor-Immune Microenvironment and Response to Radiation Therapy
Chemotherapy and radiation therapy (RT) are standard therapeutic modalities for patients with cancer, including breast cancer. Historic studies examining tissue and cellular responses to RT have predominantly focused on damage caused to proliferating malignant cells leading to their death. However, there is increasing evidence that RT also leads to significant alterations in the tumor microenvironment, particularly with respect to effects on immune cells infiltrating tumors. This review focuses on tumor-associated immune cell responses following RT and discusses how immune responses may be modified to enhance durability and efficacy of RT
Gene expression analysis reveals a different transcriptomic landscape in female and male breast cancer
Racially restricted contribution of immunoglobulin FcΞ³ and FcΞ³ receptor genotypes to humoral immunity to human epidermal growth factor receptor 2 in breast cancer
Optimized selection of anti-tumor recombinant antibodies from phage libraries on intact cells
Genetic regulation of antibody responses to human epidermal growth factor receptor 2 in breast cancer
Unique Ectopic Lymph Node-Like Structures Present in Human Primary Colorectal Carcinoma Are Identified by Immune Gene Array Profiling
We hypothesized that immune gene-related signatures would predict the presence of unique histological features of lymphoid cell infiltrates in colorectal carcinoma (CRC) that correlate with clinical parameters. Metagene analysis with gene chip technology was performed on 326 CRCs, which were then sorted by low versus high gene scores. Microscopically, CRCs with a high gene score revealed a marked host immune response organized, remarkably, as lymphoid follicles. Proliferation involved both B and T cells. In every case, the presence of CD79a+ B-cell precursors was identified, suggesting that the lymphoid follicles represent newly formed, ectopic lymph node-like structures. CD21+ dendritic cells were present within the follicular germinal centers, and CD3+ T cells were localized mainly in the parafollicular cortex zone surrounding the B-cell area of the follicles. A strong correlation between a 12-chemokine gene subset of the molecular profile and the presence of ectopic lymph node-like structures was associated with better patient survival independent of tumor staging, site location, microsatellite instability or stability, and patient treatment. These findings suggest beneficial, intratumoral immune cell priming and raise the possibility of immunotherapy intervention decisions based on molecular signatures that can identify the presence of tumor-localized, ectopic lymph node-like structures
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