The incidence and mortality of various cancers are associated with sex-specific disparities. Sex differences in cancer epidemiology are one of the most significant findings. Men are more prone to die from cancer, particularly hematological malignancies. Sex difference in cancer incidence is attributed to regulation at the genetic/molecular level and sex hormones such as estrogen. At the genetic/molecular level, gene polymorphism and altered enzymes involving drug metabolism generate differences in cancer incidence between men and women. Sex hormones modulate gene expression in various cancers. Genetic or hormonal differences between men and women determine the effect of chemotherapy. Until today, animal studies and clinical trials investigating chemotherapy showed sex imbalance. Chemotherapy has been used without consideration of sex differences, resulting in disparity of efficacy and toxicity between sexes. Based on accumulating evidence supporting sex differences in chemotherapy, all clinical trials in cancer must incorporate sex differences for a better understanding of biological differences between men and women. In the present review, we summarized the sex differences in (1) incidence and mortality of cancer, (2) genetic and molecular basis of cancer, (3) sex hormones in cancer incidence, and (4) efficacy and toxicity of chemotherapy. This review provides useful information for sex-based chemotherapy and development of personalized therapeutic strategies against cancer.

The association between inflammation and cancer has been studied widely. Indeed, the tumor microenvironment is influenced by inflammatory cells and affects tumor progression, tumor growth, and the survival of cancer cells. Also, the tumor microenvironment is essential to invasion and metastasis of cancer. Fibroblasts, immune cells, the extracellular matrix and other various components all constitute the tumor stroma, ordinarily referred to as the 'reactive stroma'. Cancer-associated fibroblasts (CAFs), which are activated fibroblasts and one of the components of the tumor microenvironment, are associated with cancer progression, invasiveness and metastasis, and their functional contributions to these processes are beginning to emerge. CAFs mediate tumor-promoting inflammation through various signaling pathways. Epithelial-mesenchymal transition is a process for producing mesenchymal cells during invasion and metastasis of cancer cells. Fibroblasts have been identified as a key player in this mechanism. In the present review, we summarize the relationships between fibroblasts, inflammatory response, the tumor microenvironment and cancer progression. This review provides useful information for the development of cancer prevention and treatment therapies through controlling the inflammatory responses.

Activation of sterol regulatory element‐binding protein 1 (SREBP‐1), a master lipogenic transcription factor, is associated with cancer metabolism and metabolic disorders. Neddylation, the process of adding NEDD8 to its substrate, contributes to diverse biological processes. Here, we identified SREBP‐1 as a substrate for neddylation by UBC12 and explored its impact on tumor aggressiveness. In cell‐based assays, SREBP‐1 neddylation prolonged SREBP‐1 stability with a decrease in ubiquitination. Consequently, NEDD8 overexpression facilitated proliferation, migration, and invasion of SK‐Hep1 liver tumor cells. MLN4924 (an inhibitor of the NEDD8‐activating enzyme‐E1) treatment or UBC12 knockdown prevented SREBP‐1 neddylation and tumor cell phenotype change. This effect was corroborated in an in vivo xenograft model. In human specimens, SREBP‐1, UBC12, and NEDD8 were all upregulated in hepatocellular carcinoma (HCC) compared to nontumorous regions. Moreover, SREBP‐1 levels positively correlated with UBC12. In GEO database analyses, SREBP‐1 levels were greater in metastatic HCC samples accompanying UBC12 upregulation. In HCC analysis, tumoral SREBP‐1 and UBC12 levels discriminated overall patient survival rates. Additionally, MLN4924 treatment destabilized SREBP‐1 in MDA‐MB‐231 breast cancer cells and in the tumor cell xenograft. SREBP‐1 and UBC12 were also highly expressed in human breast cancer tissues. Moreover, most breast cancers with lymph node metastasis displayed predominant SREBP‐1 and UBC12 expressions, which compromised overall patient survival rates. In summary, SREBP‐1 is neddylated by UBC12, which may contribute to HCC and breast cancer aggressiveness through SREBP‐1 stabilization, and these events can be intervented by MLN4924 therapy. Our findings may also provide potential reliable prognostic markers for tumor metastasis.

Sex-related incidence and outcomes were reported in various cancers, including colorectal cancer. 5-Fluorouracil (5-FU) is widely used as an essential chemotherapeutic agent for colorectal cancer. However, sexbased differences in 5-FU toxicity have yet to be reported in human cancer cell lines and xenograft mouse models to date. Here, we investigated, for the first time, sex-based differences in 5-FU toxicity using human colon cancer cell lines, xenograft mouse models, and Korean patients' data. Female-derived colon cancer cell lines exhibited greater 5-FU-induced cytotoxicity than male-derived colon cancer cell lines. We established two xenograft mouse models: one with a male-derived human colon cancer cell line injected into male mice (a male-xenograft model) and another involving a female-derived human colon cancer cell line injected into female mice (a female xenograft model). Treatment with 5-FU inhibited tumor growth and led to hematological toxicity in a female xenograft model more potently than in a male xenograft model. We analyzed the data obtained from Korean patients with colorectal cancer to examine sex differences in adverse drug reactions caused by 5-FU. Korean female patients with colorectal cancer who received 5-FU chemotherapy experienced more frequent adverse drug reactions including alopecia and leukopenia than male patients. Taken together, we demonstrated that female may be associated with increased risk of toxicity to 5-FU treatment in colorectal cancer based on in vitro and in vivo investigations and clinical data analysis. Our study suggests sex as an important clinical factor, which predicts induction of toxicity related to 5-FU treatment.

There is a wide disparity in the incidence, malignancy and mortality of different types of cancer between each sex. The sex-specificity of cancer seems to be dependent on the type of cancer. Cancer incidence and mortality have been demonstrated as sex-specific in a number of different types of cancer, such as liver cancer, whereas sex-specificity is not noticeable in certain other types of cancer, including colon and lung cancer. The present study aimed to elucidate the molecular basis for sex-biased gene expression in cancer. The mRNA expression of the epithelial-to-mesenchymal transition-associated genes was investigated, including E-cadherin (also termed CDH1), vimentin (VIM), discoidin domain receptor 1 (DDR1) and zinc finger E-box binding homeobox 1 (ZEB1) in female-and male-derived cancer cell lines by reverse transcription (RT)-PCR and the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE) database analysis. A negative correlation was observed between DDR1 and ZEB1 only in the female-derived cancer cell lines via RT-PCR analysis. A negative correlation between DDR1 index (defined by the logarithmic value of DDR1 divided by ZEB1, based on the mRNA data from the RT-PCR analysis) and an invasive phenotype was observed in cancer cell lines in a sex-specific manner. Analysis of the CCLE database demonstrated that DDR1 and ZEB1, which are already known to be sex-biased, were negatively correlated in female-derived liver cancer cell lines, but not in male-derived liver cancer cell lines. In contrast, cell lines of colon and lung cancer did not reveal any sex-dependent difference in the correlation between DDR1 and ZEB1. Kaplan-Meier survival curves using the transcriptomic datasets such as Gene Expression Omnibus, European Genome-phenome Archiva and The Cancer Genome Atlas databases suggested a sex-biased difference in the correlation between DDR1 expression pattern and overall survival in patients with liver cancer. The results of the present study indicate that sex factors may affect the regulation of gene expression, contributing to the sex-biased progression of the different types of cancer, particularly liver cancer. Overall, these findings suggest that analyses of the correlation between DDR1 and ZEB1 may prove useful when investigating sex-biased cancers.