Breast cancer is a heterogeneous disease that develops through a multistep process via the accumulation of genetic/epigenetic alterations in various cancer-related genes. Current treatment options ...for breast cancer patients include surgery, radiotherapy, and chemotherapy including conventional cytotoxic and molecular-targeted anticancer drugs for each intrinsic subtype, such as endocrine therapy and antihuman epidermal growth factor receptor 2 (HER2) therapy. However, these therapies often fail to prevent recurrence and metastasis due to resistance. Overall, understanding the molecular mechanisms of breast carcinogenesis and progression will help to establish therapeutic modalities to improve treatment. The recent development of comprehensive omics technologies has led to the discovery of driver genes, including oncogenes and tumor-suppressor genes, contributing to the development of molecular-targeted anticancer drugs. Here, we review the development of anticancer drugs targeting cancer-specific functional therapeutic targets, namely, MELK (maternal embryonic leucine zipper kinase), TOPK (T-lymphokine-activated killer cell-originated protein kinase), and BIG3 (brefeldin A-inhibited guanine nucleotide-exchange protein 3), as identified through comprehensive breast cancer transcriptomics.
Use of peptide‐based vaccines as therapeutics aims to elicit immune responses through antigenic epitopes derived from tumor antigens. Peptide‐based vaccines are easily synthesized and lack ...significant side‐effects when given in vivo. Peptide‐based vaccine therapy against several cancers including urological cancers has made progress for several decades, but there is no worldwide approved peptide vaccine. Peptide vaccines were also shown to induce a high frequency of immune response in patients accompanied by clinical efficacy. These data are discussed in light of the recent progression of immunotherapy caused by the addition of immune checkpoint inhibitors thus providing a general picture of the potential therapeutic efficacy of peptide‐based vaccines and their combination with other biological agents. In this review, we discuss the mechanism of the antitumor effect of peptide‐based vaccine therapy, development of our peptide vaccine, recent clinical trials using peptide vaccines for urological cancers, and perspectives of peptide‐based vaccine therapy.
This review describes the mechanism of the antitumor effect of peptide‐based vaccines, development of oncoantigen‐derived peptide vaccines, recent clinical trials for urological cancers using peptide‐based vaccines, and perspectives of peptide‐based therapy.
Pathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer. Large-scale studies are needed to inform future testing and variant ...classification processes in Japanese. We performed a case-control association study for variants in coding regions of 11 hereditary breast cancer genes in 7051 unselected breast cancer patients and 11,241 female controls of Japanese ancestry. Here, we identify 244 germline pathogenic variants. Pathogenic variants are found in 5.7% of patients, ranging from 15% in women diagnosed <40 years to 3.2% in patients ≥80 years, with BRCA1/2, explaining two-thirds of pathogenic variants identified at all ages. BRCA1/2, PALB2, and TP53 are significant causative genes. Patients with pathogenic variants in BRCA1/2 or PTEN have significantly younger age at diagnosis. In conclusion, BRCA1/2, PALB2, and TP53 are the major hereditary breast cancer genes, irrespective of age at diagnosis, in Japanese women.
Previous studies reported the critical role of the brefeldin A–inhibited guanine nucleotide exchange protein 3–prohibitin 2 (BIG3‐PHB2) complex in modulating estrogen signaling activation in breast ...cancer cells, yet its pathophysiological roles in osteosarcoma (OS) cells remain elusive. Here, we report a novel function of BIG3‐PHB2 in OS malignancy. BIG3‐PHB2 complexes were localized mainly in mitochondria in OS cells, unlike in estrogen‐dependent breast cancer cells. Depletion of endogenous BIG3 expression by small interfering RNA (siRNA) treatment led to significant inhibition of OS cell growth. Disruption of BIG3‐PHB2 complex formation by treatment with specific peptide inhibitor also resulted in significant dose‐dependent suppression of OS cell growth, migration, and invasion resulting from G2/M‐phase arrest and in PARP cleavage, ultimately leading to PARP‐1/apoptosis‐inducing factor (AIF) pathway activation–dependent apoptosis in OS cells. Subsequent proteomic and bioinformatic pathway analyses revealed that disruption of the BIG3‐PHB2 complex might lead to downregulation of inner mitochondrial membrane protein complex activity. Our findings indicate that the mitochondrial BIG3‐PHB2 complex might regulate PARP‐1/AIF pathway–dependent apoptosis during OS cell proliferation and progression and that disruption of this complex may be a promising therapeutic strategy for OS.
In this study, we focused on understanding the critical role of the mitochondrial BIG3‐PHB2 complex in osteosarcoma (OS) cell proliferation and survival. Its complex disruption by the specific dominant‐peptide inhibitor causes mitochondrial dysfunction, resulting in apoptotic cell death and decreases in the migration and invasion abilities of OS cells. These findings suggest that inhibiting the BIG3‐PHB2 complex formation may be a new therapeutic strategy for the treatment of OS.
We previously reported that upregulation of SMYD3, a histone H3 lysine‐4‐specific methyltransferase, plays a key role in the proliferation of colorectal carcinoma (CRC) and hepatocellular carcinoma ...(HCC). In the present study, we reveal that SMYD3 expression is also elevated in the great majority of breast cancer tissues. Similarly to CRC and HCC, silencing of SMYD3 by small interfering RNA to this gene resulted in the inhibited growth of breast cancer cells, suggesting that increased SMYD3 expression is also essential for the proliferation of breast cancer cells. Moreover, we show here that SMYD3 could promote breast carcinogenesis by directly regulating expression of the proto‐oncogene WNT10B. These data imply that augmented SMYD3 expression plays a crucial role in breast carcinogenesis, and that inhibition of SMYD3 should be a novel therapeutic strategy for treatment of breast cancer. (Cancer Sci 2006; 97: 113 – 118)
Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12‐18 months. Frizzled homolog 10 (FZD10) is ...overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of β‐radioimmunotherapy (RIT) with the 90Y‐labeled anti‐FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α‐RIT with OTSA101 labeled with the α‐emitter 225Ac. Competitive inhibition and cell binding assays showed that specific binding of 225Ac‐labeled OTSA101 to SYO‐1 synovial sarcoma cells was comparable to that of the imaging agent 111In‐labeled OTSA101. Biodistribution studies showed high uptake in SYO‐1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225Ac‐labeled OTSA101 for tumors was 7.8 Bd higher than that of 90Y‐labeled OTSA101. 90Y‐ and 225Ac‐labeled OTSA101 decreased tumor volume and prolonged survival. 225Ac‐labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225Ac‐labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90Y‐labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment‐related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225Ac‐labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO‐1. RIT with 225Ac‐labeled OTSA101 is a promising therapeutic option for synovial sarcoma.
FZD10‐targeted alpha‐radioimmunotherapy with 225Ac‐labeled OTSA101 provided a high radiation dose to tumors and achieved 60% complete response in the synovial sarcoma mouse model SYO‐1. This is the best outcome among FZD10‐targeted therapy to date. Our alpha‐radioimmunotherapy would provide an additional therapeutic option to synovial sarcoma patients that do not show a good response to conventional therapy.
In the thymus, the thymic epithelium provides a microenvironment essential for the development of functionally competent and self-tolerant T cells. Previous findings showed that modulation of ...Wnt/β-catenin signaling in mouse thymic epithelial cells (TECs) disrupts embryonic thymus organogenesis. However, the role of β-catenin in TECs for postnatal T-cell development remains to be elucidated. Here, we analyzed gain-of-function (GOF) and loss-of-function (LOF) of β-catenin highly specific in mouse TECs. We found that GOF of β-catenin in TECs results in severe thymic dysplasia and T-cell deficiency beginning from the embryonic period. By contrast, LOF of β-catenin in TECs reduces the number of cortical TECs and thymocytes modestly and only postnatally. These results indicate that fine-tuning of β-catenin expression within a permissive range is required for TECs to generate an optimal microenvironment to support postnatal T-cell development.
Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) interacts with and inhibits the tumor suppressor function of prohibitin-2 (PHB2), and recent in vivo studies have demonstrated that ...the BIG3-PHB2 interaction is a promising target for breast cancer therapy. However, little biophysical characterization on BIG3 and its interaction with PHB2 has been reported. Here we compared the calculated 8-class secondary structure of the N-terminal domains of BIG family proteins and identified a loop region unique to BIG3. Our biophysical characterization demonstrated that this loop region significantly affects the colloidal and thermodynamic stability of BIG3 and the thermodynamic and kinetic profile of its interaction with PHB2. These results establish a model for the BIG3-PHB2 interaction and an entry for drug discovery for breast cancer.
•The interaction between BIG3 and PHB2 was characterized by using ITC and SPR.•Non-conserved loop region of BIG3 affects the colloidal and thermodynamic stability of BIG3.•A mutein of the non-conserved loop BIG3 (1-373Δloop) showed higher binding affinity.•The N-terminal domain of BIG3 is regulated via the molecular states of the unique loop region.
To elucidate the molecular mechanisms of mammary carcinogenesis and discover novel therapeutic targets for breast cancer, we previously carried out genome‐wide expression profile analysis of 81 ...breast cancer cases by means of cDNA microarray coupled with laser microbeam microdissection of cancer cells. Among the dozens of transactivated genes, in the present study we focused on the functional significance of kinesin family member 2C (KIF2C)/mitotic centromere‐associated kinesin (MCAK) in the growth of breast cancer cells. Northern blot and immunohistochemical analyses confirmed KIF2C/MCAK overexpression in breast cancer cells, and showed that it is expressed at undetectable levels in normal human tissues except the testis, suggesting KIF2C/MCAK to be a cancer–testis antigen. Western blot analysis using breast cancer cell lines revealed a significant increase in the endogenous KIF2C/MCAK protein level and its phosphorylation in G2/M phase. Treatment of breast cancer cells with small interfering RNA against KIF2C/MCAK effectively suppressed KIF2C/MCAK expression and inhibited the growth of the breast cancer cell lines T47D and HBC5. In addition, we found that KIF2C/MCAK expression was significantly suppressed by ectopic introduction of p53. These findings suggest that overexpression of KIF2C/MCAK might be involved in breast carcinogenesis and is a promising therapeutic target for breast cancers. (Cancer Sci 2008; 99: 62–70)
Analysis of anticancer immunity aids in assessing the prognosis of patients with breast cancer. From 250 operated breast cancers, we focused on serum levels of C‐C motif chemokine ligand 5 (CCL5), ...which is involved in cancer immune reactions. Serum levels of CCL5 were measured using a cytometric bead‐based immunoassay kit and CCL5 expression in cancer cells was determined using immunohistochemical staining. In addition, mRNA in cancer and stromal cells was analyzed by microdissection and comparison with the public dataset. Disease‐free survival (DFS) of patients with high CCL5 levels (cut‐off, 13.87 ng/mL; n = 192) was significantly better than those with low CCL5 levels (n = 58; hazard ratio, 0.20; 95% confidence interval, 0.10‐0.39; P < .0001). An improved overall survival was observed in patients with high CCL5 levels compared to those with low CCL5 levels (P = .024). On the contrary, high immunohistochemical expression of CCL5 in cancer cells was significantly associated with decreased DFS. As serum CCL5 levels did not correlate with CCL5 expression in cancer cells and the relative expression of mRNA CCL5 was elevated in stromal cells in relation to cancer cells, serum CCL5 might be derived not from cancer cells, but from stromal cells. Expression of CCL5 in serum, but not in cancer cells, might contribute to improved patient prognosis mediating through not only immune reaction, but through other mechanisms. Determination of circulating CCL5 levels could be useful for predicting patient prognosis.
We found that high levels of serum C‐C motif chemokine ligand 5 (CCL5), a chemokine produced by immune cells, were significantly associated with improved prognosis of patients with operated breast cancer. As the relative expression of mRNA CCL5 was elevated in stromal cells, serum CCL5 seems to be derived not from cancer cells, but from stromal cells. CCL5 might contribute to improved patient prognosis mediating through not only immune reaction, but through other mechanisms.
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