Hereditary breast and ovarian cancers (HBOC) carry a high risk of breast cancer, and detailed screening with contrast-enhanced breast MRI (breast MRI surveillance) is recommended. With the increase in the number of individuals diagnosed with HBOC, the demand for breast MRI surveillance is also rising. However, the current system is inadequate, with factors such as lack of knowledge and indifference among healthcare professionals, and insufficient understanding of breast MRI surveillance being cited. This study aims to investigate the knowledge of HBOC and the awareness of breast MRI surveillance among radiological technologists, and to analyze the factors that promote these practices.

Castration-resistant prostate cancer and multiple lymph node and ventral bladder metastases in an 87 year-old man progressed despite various systemic therapies, including chemotherapy. Because his prostate surgical specimen displayed a microsatellite instability (MSI) -high status, pembrolizumab 200 mg/body treatment was started. After six courses of treatment, his prostate-specific antigen (PSA) level decreased by 83% versus that at treatment initiation (from 408.78 ng/ml to 69.54 ng/ml), and the para-aortic lymph node metastasis was reduced in size on imaging. After 13 courses, his PSA level (462.59 ng/ml) exceeded that at the start of treatment, and progressive disease was detected on imaging. Although case reports of pembrolizumab for MSI-high prostate cancer remain few because of its rarity, it is an important therapeutic option and further clinical research is required.

Chronic activation of the nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARA), causes hepatocellular proliferation and increases the incidence of hepatocellular carcinoma in rodents. However, the molecular mechanisms underlying hepatocyte proliferation by activated PPARA remain ambiguous. This review focuses on the genes repressed by PPARA and describes the mechanism by which it promotes hepatocyte proliferation in mice. PPARA undergoes autoinduction, leading to its overexpression by an agonist. PPARA subsequently activates the E2F transcription factor 8 (E2f8), which then activates the ubiquitin-like protein containing the PHD and RING finger domains 1 (Uhrf1). UHRF1, in complex with histone deacetylase 1 and DNA methyltransferase 1, stimulates DNA methylation and recruitment of histone H3 containing trimethylated lysine 9 to the promoters of specific target genes, including E-cadherin/cadherin 1 (Cdh1), resulting in their downregulation. Decreased expression of CDH1 stimulates Wnt signaling, upregulation of oncogenes, including Myc and the cell cycle control genes, cyclin D1 and Jun, and enhances hepatocyte hyperproliferation. Therefore, the PPARA-E2F8-UHRF1-CDH1-Wnt signaling axis is involved in the epigenetic regulation of hepatocyte proliferation. This review provides insights into the mechanisms underlying hepatocarcinogenesis induced by non-genotoxic substances.

Since commencing my role as a professor in a newly established Department of Pharmacodynamics and Molecular Genetics at the School of Pharmacy, Iwate Medical University, on April 1, 2007, my research has focused on modifying gene expression of cytochrome P-450 (CYP) in established human colon cancer cells. Additionally, I have been investigating methods to enhance the anti-tumor effects of irinotecan (CPT-11) and 5-fluorouracil (5-FU) using epigenetic modifying inhibitors of DNA methyltransferase and histone deacetylase. Treating colon cancer cells with a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (DAC), led to elevated expression levels of CYP1B1 and CYP3A4 through demethylation of the promoter regions of related genes. Furthermore, the administration of DAC and the histone deacetylase inhibitor depsipeptide [(DEP), an anti-cancer drug romidepsin] significantly increased the cellular sensitivities of human colon cancer cells to CPT-11 and 5-FU, respectively. Remarkably, DAC treatment also increased colon cancer cell sensitivity to SN-38, an active metabolite of CPT-11, through the suppression of the anti-apoptotic protein Bcl-2. DEP increased colon cancer cell sensitivity to 5-FU in association with increased expressions of tumor-suppressor p21 and major histocompatibility complex class II genes. Another facet of my research is centered around understanding the gene regulatory mechanisms of the CYP1 family through aryl hydrocarbon receptors (AhR)s under glucose-deprivation stress and in three-dimensional (3D) culture systems of human solid tumor cells. In the 3D culture of human liver cancer cells, I found Pregnane X Receptor being implicated in the regulation of CYP1A2, which aligns with the in vivo mode of CYP1A2 expression.

A 75-year-old man presented with macroscopic hematuria and a high serum prostate-specific antigen (PSA) level. Macroscopic hematuria had subsided by the time of consultation. The PSA level was 38.590 ng/ml, which, along with rectal examination and magnetic resonance imaging findings, led to the suspicion of prostate cancer. Transrectal needle biopsy of the prostate revealed intraductal carcinoma of the prostate (IDC-P). Computed tomography and bone scintigraphy were performed, and the prostate cancer was classified as cT2cN0M0. After 6 months of combined androgen blockade therapy, a radical prostatectomy was performed; however, PSA levels continued to increase, and the patient was diagnosed with castration resistant prostate cancer. Multiple bone metastases appeared 5 months after the initiation of abiraterone therapy. Three courses of docetaxel and two courses of cabazitaxel were administered, but the disease progression continued. The IDC-P was found to be positive for the BRCA2 mutation by BRACAnalysis® performed at the start of cabazitaxel therapy. To our knowledge, no other cases of BRCA2 mutation positive IDC-P have been reported in Japan. After we started administration of Olaparib, the patient's PSA level was lowered and the disease progression stopped.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). It is characterized by skin tumors, multiple lung cysts, and renal tumors. Active genetic testing and appropriate periodic examinations of family lines of patients with BHD syndrome have not been widely performed. In this report, we present our experience regarding the diagnosis of asymptomatic family members with BHD syndrome. The proband was a 65-year-old female with a family history of colorectal cancer and spontaneous pneumothorax that affected her father. Computed tomography revealed an approximately 10 cm-sized tumor protruding from the upper pole of the left kidney, a buried tumor approximately 1.5 cm in length in the right kidney, and multiple pulmonary cysts. The patient underwent laparoscopic radical left nephrectomy. Pathological examination indicated that the resected tumor was a chromophobe renal cell carcinoma. After the surgery, there was no evidence of local recurrence or metastasis. The size of the tumor in the right kidney was monitored, but it did not increase. On FLCN genetic examination, targeted next generation sequencing revealed a partial deletion of exon 14, thus confirming the diagnosis of the patient to be BHD syndrome that caused the previously unreported pathogenic variant. Three years after the surgery, we conducted genetic counseling for the proposita and her three children. Genetic examination, performed at the request of the second daughter, confirmed that she carried the same genetic variant as her mother. This diagnosis prompted the second daughter to begin managing her health via periodic imaging tests.

Although molecular targeted drugs are significantly effective in many types of cancer treatment, almost all patients suffer from drug resistance. For instance, non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation invariably develop resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and melanoma patients with BRAF mutation develop resistance to BRAF inhibitors. Mechanistically, genetic and irreversible resistance mechanisms have been studied for more than a decade, while non-mutational and reversible resistance mechanisms are yet to be clearly understood. Since drug tolerant persisters (DTPs), which emerge at the beginning of the drug treatment, have been reported in 2010, several non-mutational tolerance mechanisms have been reported by various researchers. Furthermore, with the advancement in single cell sequencing technology, increasing attention has been drawn towards the investigation of the heterogeneous characteristics of drug tolerant cell populations. Here, we describe the recent advances in non-mutational drug tolerant mechanisms toward the molecular targeted drugs. In our study, we tried to elucidate the unconventional resistance mechanisms by utilizing newly approved EGFR-TKI, dacomitinib. Our established drug resistant cells did not gain new mutation in EGFR even after long time exposure to the drug. In addition, the drug resistance vanished when resistant cells were implanted in mice, which indicates that mechanisms conferring drug sensitivity might be host-dependent. Thus, our study may provide a new insight into non-mutational drug tolerant mechanisms.

ATP-binding cassette (ABC) transporters, which comprise the largest gene-family in humans, are membrane proteins that transport various substrates, depending on ATP hydrolysis. Among these transporters, several include ABCB1 (P-glycoprotein), identified here for the first time in humans, which exports anti-cancer drugs from cancer cells, thus participating in multidrug resistance (MDR). ABC transporters also export drugs, in general, from the human body, therefore affecting overall pharmacokinetics. We have contributed, here, to a better understanding of the role of these exporter proteins in two aspects. First, we have cloned the human ABCC2 gene and identified mutations in hereditary hyperbilirubinemia patients, demonstrating the role of ABCC2 as a xenobiotic export pump. Second, we also found an unexpected role of ABCB1 in cancer, in that it promotes tumor initiation independently of the MDR phenomenon, which was further confirmed by a chemoprevention experiment using verapamil, an ABCB1 inhibitor. In this review, I discuss the role of ABC transporters, both in biodefense against xenobiotics and in cancer development and malignant alterations, based on our results as well as the studies of others.

Humans are continually exposed to various chemicals in the environment. Some of these environmental chemicals not only induce malignant transformation but also enhance the malignant potential of the cancer. In this review, the author summarizes the findings on the effects of environmental chemicals on cancer with a focus on inorganic cadmium (Cd) and organic bisphenol A (BPA). Cd, an established human carcinogen, enhances the invasive capacity of rat liver TRL 1215 cells during malignant transformation by downregulating apolipoprotein E (ApoE), a suppressor of cell invasion, via induction of DNA hypermethylation in its promoter region by the oxidative stress/ten-eleven translocation methylcytosine dioxygenase 1 (TET1)-mediated machinery. BPA, which is recognized as an endocrine disruptor, raises the concern that very high concentrations (beyond environmental levels) of BPA are required for activation of estrogen receptors α/β (ERα/β) in vitro. We identified a BPA metabolite, 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), which exhibited more potent estrogenic activity than BPA. Thus, MBP may be a key candidate for explaining the endocrine-disrupting effects of BPA. In addition, the estrogenic action of MBP can be enhanced by repeated exposure of MCF-7 cells to the actualized ERβ subtype because of the downregulation of ERα in human breast cancer MCF-7 cells. MBP downregulates the expression of the tumor suppressor gene, G protein-coupled estrogen receptor 1 (GPER1), via ERβ signaling.

A 36-year-old man presented with painless swelling in the right side scrotum. Ultrasonography showed a hypoechoic tumor with mosaic pattern. Plain computed tomograghy (CT) revealed a 67 mm scrotal cystic lesion with low density area. We suspected an intrascrotal tumor and performed right side radical orchiectomy. The removed sample was yellow clear and elastic hard. A 7 cm multilocular cystic tumor was present on the head side of the normal testis. The cut-surface and the contents of the mass revealed a jelly-like viscous liquid. On the microscopic examination, the tumor was composed of mucinous stroma and spindle-shaped atypical cells with hyperchromatic oval nuclei and eosinophilic cytoplasm. There was a characteristic network of blood vessesls with hyperhyalinization in the myxoid zones. Immunohistochemically, CDK4, MDM2, AE1/AE3, S-100, Alpha-SMA and desmin were negative, but MUC4 showed focal cytoplasmic positivity in the neoplastic cells. In the reverse transcription polymerase chain reaction assay, no FUS-CREB3L2/FUS-CREB3L1 fusion transcripts were identified although the detectable messages of the housekeeping genes were noted. The tumour was finally diagnosed as a paratesticular low-grade fibromyxoid sarcoma. Postoperative course was uneventful and no recurrence or metastasis was seen four months after the operation.

Various reports have been published in recent years on the effects of histone deacetylase (HDAC) inhibitors on programmed death ligand 1 (PD-L1) expression in cancer cells. The combination therapy of immune checkpoint inhibitors and HDAC inhibitors utilizing these effects has attracted attention as a new clinical treatment of triple-negative breast cancers. We investigated how the expression level of PD-L1 changes depending on the type of HDAC inhibitor exposed to triple-negative breast cancer cell line MDA-MB-231. We found that the mRNA expression level of PD-L1 was significantly decreased by Vorinostat and K-32 (pan-HDAC inhibitors) at high concentrations exhibiting low cell viability, while it was increased by high concentrations of K-560 (HDAC1,2 inhibitor) and Entinostat (HDAC1,3 inhibitor). On the other hand, the mRNA level of PD-L1 was increased by all of these HDAC inhibitors at low concentrations showing high cell viability. Of particular note, K-32 induced more PD-L1 mRNA than all the other HDAC inhibitors at the lowest concentration of 0.5 μM. This finding might suggest the usefulness of pan-HDAC inhibitors in clinical treatment in combination with immune checkpoint inhibitors.

Exposure to ionizing radiation (IR) increases the risk of cancers, as epidemiology studies of atomic bomb survivors and patients who have received radiotherapy show. The carcinogenic effects of IR are well-documented, although the effects of radiation carcinogenesis change in each organ. The mammary gland is known to be highly susceptible to radiation-induced cancer. We have previously reported that (i) differential DNA methylation patterns in rat mammary carcinomas induced by pre-and post-pubertal IR; (ii) the effect of parity on rat mammary carcinogenesis varies between pre-and post-pubertal IR. In this review, we summarize our radiation researches as well as related with other radiation researches in rodent models.

Epithelial-mesenchymal transition (EMT) is an important program in epithelial cancer cells to acquire the motility and invasion, which promotes cancer metastasis to remote organs. EMT is induced by various secreted factors, such as transforming growth factor-β (TGF-β) and epidermal growth factor (EGF). TGF-β ligand activates Smad-dependent and -independent pathways by binding to TGF-β receptors. In Smad-dependent pathway, the activated TGF-β receptor phosphorylates Smad2/3 and accelerates its association with Smad4, leading to their nuclear translocation. Smad2/3-4 complex promotes the expression of EMT-inducing transcription factors, such as Snail and Slug. In Smad-independent pathway, mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways are activated and required for TGF-β-induced EMT. Smad-independent pathway is similar to downstream of receptor tyrosine kinases, and therefore EGFR signaling is known to induce EMT synergize with TGF-β signaling. We explored a new mechanism of EGFR-mediated activation of TGF-β signaling and found that c-Abl kinase activates TGF-β signaling. Based on our proteomic analysis, we identified several TGF-β signaling molecules as nuclear c-Abl substrates, including transcriptional intermediary factor 1-γ (TIF1γ/TRIM33/Ectodermin), a suppressor of TGF-β signaling. c-Abl-mediated phosphorylation of TIF1γ inhibits its binding to Smad3, thereby increasing Smad3's transcriptional activity and promoting EMT. TIF1γ phosphorylation is also involved in the EGFR-caused aberrant activation of TGF-β signaling, suggesting that EGFR/c-Abl pathway activates TGF-β signaling through phosphorylation of nuclear substrates and promotes EMT. Our findings provide new insights into the activation machinery of TGF-β signaling, and further studies are required to clarify the clinical significance of the EGFR/c-Abl pathway in cancer metastasis.

Lynch syndrome (LS) is an autosomal dominant genetic disorder in which tumors are known to develop at an early age. Upper tract urothelial carcinoma is one of the tumors related to Lynch syndrome. A 49-year-old woman visited a urologic clinic due to left abdominal pain. She had a history of ovarian cancer. Her mother had a history of colorectal cancer and renal pelvic cancer, and her grandmother had had colorectal cancer. After detailed examination, she received laparoscopic left nephroureterectomy and she was pathologically diagnosed with left ureteral cancer. LS was suspected based on her past history, family history, and age. A microsatellite instability (MSI) test gave a positive result, and genetic analysis confirmed a mutation in the MSH2 gene, leading to the diagnosis of Lynch syndrome. Although LS has a high frequency of carcinogenesis, it is thought that an improved prognosis can be achieved by early discovery and treatment of cancer in LS patients. From our case report, we recommend screening of LS in patients with a past/family history, who have had an upper tract urothelial carcinoma. Once LS is diagnosed, the patient should be followed by a planned surveillance of cancer development.

Nutrients are essential for all living organisms. Because growing cancer cells have strong metabolic demands, nutrient transporters are constitutively increased to facilitate the nutrient uptake. Among these nutrient transporters, L-type amino acid transporter 1 (LAT1), which transports large neutral amino acids including essential amino acids, is critical for cancer growth. Therefore, LAT1 has been considered as an attractive target for diagnosis and therapy of cancers. We have developed several lines of compounds for cancer diagnosis and therapy. To diagnose cancer by using positron emission tomography (PET) probes, we have created amino acid derivatives which are selectively transported by LAT1 and accumulated in cancer cells. In addition to amino acid derivatives as the LAT1 inhibitors, we also have made non-amino acid small compounds as anti-cancer drugs which inhibit LAT1 function and suppress tumor growth. The LAT1 targeting anti-cancer drug showed low toxicity but strong effects on various types of cancer cells in animal models. The novel PET probe is approved for clinical research and the new anti-cancer drug has been under clinical trial. Small compounds targeting the amino acid transporter bring us new tools for cancer diagnosis and therapy.

Target molecules of existing anti-cancer therapeutic monoclonal antibodies (mAbs) are divided into 1) receptor-type tyrosine kinases, such as human epidermal growth factor receptor (HER) family, 2) differentiation antigens, such as CD20 (Rituxan target), 3) angiogenesis-related molecules, and 4) immune checkpoint molecules (PD-1, etc.). We have recently reported a novel therapy targeting lymphangiogenesis, but not angiogenesis, using an anti-LYVE-1 (lymphatic vessel endothelial hyaluronan receptor 1) mAb. At present, many transporters are not considered to be target molecules for the cancer therapy; however, our study strongly suggested that the inhibition of cancer metabolism by mAbs against amino acid transporters will play a significant role in future cancer therapies. Most anti-cancer therapeutic mAbs bind cell-surface molecules on viable cancer cells: therefore, it is necessary to produce mAbs recognizing epitopes on the extracellular domains of native and non-denatured proteins. We concluded that viable cancer cells or cells transfected with cDNA encoding target proteins are suitable immunogens for the production of anti-cancer therapeutic mAbs. We introduce our efforts to develop seeds for therapeutic mAbs using whole cancer cells and transfectants as the immunogen. As many target candidates in the future are multi-pass membrane proteins, such as 12-pass amino acid transporter proteins belonging to the solute carrier (SLC) family, and their possible immunogenic extracellular regions are small, the production of specific mAbs is highly difficult. In this review, we summarize the successful preparation and characterization of mAbs recognizing the extracellular domain of oncoproteins, including transporters.

Among breast cancer cases, 5-10% are thought to have germline mutations in genes associated with onset. Among these, hereditary breast cancer-ovarian cancer syndrome, which develops from breast cancer susceptibility (BRCA) gene mutation, has become widely known. Since 2018, olaparib has been clinically available for patients with inoperable or recurrent breast cancer. However, to use this medicine, BRCA gene mutation must be confirmed. Our hospital has prepared a BRCA genetic testing procedure, counseling system, and environment for the safe use of olaparib for BRCA genetic mutation positive patients. Until patients get the results of the BRCA gene examination, the attending physician and certified in breast cancer nurse care for the patient. If a positive result is obtained, we have established cooperation with a neighboring hospital, since our hospital cannot provide the genetic counseling. The main role of pharmacists is to develop a description system, as with other therapeutic agents, and to develop measures to help with supportive care for side effects. Also important is the development of a system to provide information to community pharmacies. At this symposium, we will report on how we developed our treatment strategy for patients with hereditary breast cancer syndrome, and the integrated role of pharmacists at Hamamatsu Medical Center.

We established an outpatient service in November 2017 to provide cancer gene profiling test services to cancer patients. To date, we have seen approximately 100 patients. Our staff includes genetic counselors and nurses specialized in genetic medicine. Our experience highlights the importance of healthcare professionals having in-depth knowledge of cancer therapeutic drugs and/or investigational drugs based on cancer genome medicine. Recently, poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for treating breast cancer patients with germline BRCA mutation; thus, in-depth knowledge of genetics and skills for genetic counseling are often considered indispensable in working with cancer patients. However, because the prompt treatment of clear and present cancer is the top priority in clinical settings, providing genetic information at that time, including that of unaffected family members, is of low priority for most patients who are dealing with the severe side effects of anti-cancer therapies. Pharmacists have an essential role to play in cancer therapeutics, talking with patients in order to assess their condition and to clarify the status of their treatment with anticancer agents. Genetic pharmacists should therefore work closely with genetics nurses and genetic counselors in the clinical practice of cancer genomic medicine. In this symposium, I would like to describe our experience caring for patients through our outpatient service, and to discuss the ideal framework for multidisciplinary cooperation to promote cancer genomic medicine.

The development of cancer genomic medicine has been embraced as an important new policy issue in "The 3rd Basic Plan to Promote Cancer Control Programs" formulated by the Japanese government. Cancer-associated gene panel testing has been recognized by the public health insurance system since July 2019, and is a critical component of the clinical implementation of genomic science. Because of this dynamic change in cancer medicine, pharmacists are now expected to acquire knowledge about genomic science, and to apply it to individualized and appropriate pharmacotherapies. This review outlines the roles of pharmacists in cancer genomic medicine.