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Nuclear receptors (NRs) represent intracellular proteins that function as a signaling network of transcriptional factors to control genes in response to a variety of environmental, dietary, and hormonal stimulations or serve as orphan receptors lacking a recognized ligand. They also play an essential role in normal development, metabolism, cell growth, cell division, physiology, reproduction, and homeostasis and function as biological markers for tumor subclassification and as targets for hormone therapy. NRs, including steroid hormone receptors (SHRs), have been studied as tools to examine the fundamentals of transcriptional regulation within the development of mammals and human physiology, in addition to their links to disturbances. In this regard, it is widely recognized that aberrant NR signaling is responsible for the pathological growth of hormone-dependent tumors in response to SHRs dysregulation and consequently represents a potential therapeutic candidate in a range of diseases, as in the case of prostate cancer and breast cancer. On the other hand, phytosterols are a group of plant-derived compounds that act directly as ligands for NRs and have proven their efficacy in the management of diabetes, heart diseases, and cancers. However, these plants are not suggested in cases of hormone-dependent cancer since a certain group of plants contains molecules with a chemical structure similar to that of estrogens, which are known as phytoestrogens or estrogen-like compounds, such as lignans, coumestans, and isoflavones. Therefore, it remains an open and controversial debate regarding whether consuming a phytosterol-rich diet and adopting a vegetarian lifestyle like the Mediterranean diet may increase the risk of developing steroid hormone-dependent cancers by constitutively activating SHRs and thereby leading to tumor transformation. Overall, the purpose of this review is to better understand the relevant mechanistic pathways and explore epidemiological investigations in order to establish that phytosterols may contribute to the activation of NRs as cancer drivers in hormone-dependent cancers.

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Increasing attention has been paid to the biological roles of tripartite motif-containing (TRIM) family proteins, which typically function as E3 ubiquitin ligases. Estrogen-responsive finger protein (Efp), a member of the TRIM family proteins, also known as TRIM25, was originally identified as a protein induced by estrogen and plays critical roles in promoting endocrine-related cancers, including breast cancer, endometrial cancer, and prostate cancer. The pathophysiological importance of Efp made us interested in the roles of other TRIM family proteins that share a similar structure with Efp. Based on a phylogenetic analysis of the C-terminal region of TRIM family proteins, we focused on TRIM47 as a protein belonging to the same branch as Efp. TRIM47 is a poor prognostic factor in both breast cancer and prostate cancer. Atypical lysine-27-like poly-ubiquitination was involved in the underlying mechanism causing endocrine resistance in breast cancer. We also discuss the functions of Efp and TRIM47 in other types of cancers and innate immunity by introducing substrates the are modified by poly-ubiquitination.

Endocrine Disrupting Compounds (EDCs) are found in everyday products. Widely distributed throughout the environment, persistent organic pollutants (POPs) are a specific class of EDCs that can accumulate in adipose tissue. Many of them induce adverse effects on human health-such as obesity, fertility disorders and cancers-by perturbing hormone effects. We previously identified many compounds with EDC activity in the circulation of obese patients who underwent bariatric surgery. Herein, we analyzed the effects of four of them (aldrin, BDE28, PFOA and PCB153) on two cancer cell lines of hormone-sensitive organs (prostate and breast). Each cell line was exposed to serial dilutions of EDCs from 10-6 M to 10-12 M; cytotoxicity and proliferation were monitored using the IncuCyte® technology. We showed that none of these EDCs induce cytotoxicity and that PFOA and PCB153, only at very low doses (10-12 M), increase the proliferation of DU145 (prostate cancer) and MCF7 (breast cancer) cells, while the same effects are observed with high concentrations (10-6 M) for aldrin or BDE28. Regarding the mechanistic aspects, PFOA uses two different signaling pathways between the two lines (the Akt/mTORC1 and PlexinD1 in MCF7 and DU145, respectively). Thus, our study demonstrates that even at picomolar (10-12 M) concentrations PFOA and PCB153 increase the proliferation of prostate and breast cancer cell lines and can be considered possible carcinogens.

Malignancies dependent on hormone homeostasis include breast, ovary, cervical, prostate, testis and uterine tumors. Hormones are involved in signal transduction which orchestrate processes, such as apoptosis, proliferation, cell cycle or cytoskeleton organization. Currently, there is a need for novel biomarkers which would help to diagnose cancers efficiently. In this study, the genes implicated in signaling that is important in hormone-sensitive carcinogenesis were investigated regarding their prognostic significance. Data of seven cancer cohorts were collected from FireBrowse. 54 gene sets implicated in specific pathways were browsed through MSig database. Profiling was assessed via Monocle3, while gene ontology through PANTHER. For confirmation, correlation analysis was performed using WGCNA. Protein-protein networks were visualized via Cytoscape and impact of genes on survival, as well as cell cycle or cytoskeleton-related prognostic signatures, was tested. Several differences in expression profile were identified, some of them allowed to distinguish histology. Functional annotation revealed that various regulation of cell cycle, adhesion, migration, apoptosis and angiogenesis underlie these differences. Clinical traits, such as histological type or cancer staging, were found during evaluation of module-trait relationships. Of modules, the TopHubs (COL6A3, TNR, GTF2A1, NKX3-1) interacted directly with, e.g., PDGFB, ITGA10, SP1 or AKT3. Among TopHubs and interacting proteins, many showed an impact on hazard ratio and affected the cell cycle or cytoskeleton-related prognostic signatures, e.g., COL1A1 or PDGFB. In conclusion, this study laid the foundation for further hormone-sensitive carcinogenesis research through identification of genes which prove that crosstalk between cell cycle and cytoskeleton exists, opening avenues for future therapeutic strategies.

The discovery of microRNAs (miRNAs) has fundamentally transformed our understanding of gene regulation. The competing endogenous RNA (ceRNA) hypothesis postulates that messenger RNAs and other RNA transcripts, such as long non-coding RNAs and pseudogenes, can act as natural miRNA sponges. These RNAs influence each other\'s expression levels by competing for the same pool of miRNAs through miRNA response elements on their target transcripts, thereby modulating gene expression and protein activity. In recent years, these ceRNA regulatory networks have gained considerable attention in cancer research. Several studies have identified cancer-specific ceRNA networks. Nevertheless, prior bioinformatic analyses have focused on long-non-coding RNA-associated ceRNA networks. Here, we identify an extended ceRNA network (including both long non-coding RNAs and pseudogenes) shared across a group of five hormone-dependent (HD) cancers, i.e., prostate, breast, colon, rectal, and endometrial cancers, using data from The Cancer Genome Atlas (TCGA). We performed a functional enrichment analysis for differentially expressed genes in the shared ceRNA network of HD cancers, followed by a survival analysis to determine their prognostic ability. We identified two long non-coding RNAs, nine genes, and seventy-four miRNAs in the shared ceRNA network across five HD cancers. Among them, two genes and forty-one miRNAs were associated with at least one HD cancer survival. This study is the first to investigate pseudogene-associated ceRNAs across a group of related cancers and highlights the value of this approach to understanding the shared molecular pathogenesis in a group of related diseases.

Sex hormone-dependent cancers currently contribute to the high number of cancer-related deaths worldwide. The study and elucidation of the molecular mechanisms underlying the progression of these tumors was a double-edged sword, leading to the expansion and development of new treatment options, with the cost of triggering more aggressive, therapy resistant relapses. The interaction of androgen, estrogen and progesterone hormones with specific receptors (AR, ER, PR) has emerged as a key player in the development and progression of breast, ovarian, prostate and endometrium cancers. Sex hormone-dependent cancers share a common and rather unique carcinogenesis mechanism involving the active role of endogenous and exogenous sex hormones to maintain high mitotic rates and increased cell proliferation thus increasing the probability of aberrant gene occurrence and accumulation highly correlated with abnormal cell division and the occurrence of malignant phenotypes. Cancer related hormone therapy has evolved, currently being associated with the blockade of other signaling pathways often associated with carcinogenesis and tumor progression in cancers, with promising results. However, despite the established developments, there are still several shortcomings to be addressed. Triterpenes are natural occurring secondary metabolites biosynthesized by various pathways starting from squalene cyclization. Due to their versatile therapeutic potential, including the extensively researched antiproliferative effect, these compounds are most definitely a cornerstone in the research and development of new natural/semisynthetic anticancer therapies. The present work thoroughly describes the ongoing research related to the antitumor activity of triterpenes in sex hormone-dependent cancers. Also, the current review highlights both the biological activity of various triterpenoid compounds and their featured mechanisms of action correlated with important chemical structural features.

The aim of the current study was first to investigate cytotoxic activity of usnic acid (UA) on hormone-dependent breast and prostate cancer, and normal cells. Cells were treated with increasing concentrations (25 to 150 µM) of UA for 48 hours and cell viability, quantitative and morphological analysis of cell death, and cell cycle analysis were performed. UA was shown to have selective cytotoxicity on hormone-dependent cancer cells with the IC50 levels of 71.4 and 77.5 µM for MCF7 and LNCaP cells, respectively. UA induced apoptotic cell death and G0/G1 cell cycle arrest without damaging normal cells. MCF7 cells were more sensitive to UA than LNCaP cells. Our results first revealed that UA is a promising candidate as an alternative agent for hormone-dependent breast and prostate cancers. However, molecular mechanism underlying the UA-mediated cell death in cancer cells should be investigated further.

The tyrosine kinase receptor c-KIT and its ligand, the stem cell factor (SCF) are expressed in several tissues of male and female reproductive tract, playing an important role in the regulation of basic biological processes. The activation of c-KIT by SCF controls, cell survival and death, cell differentiation and migration. Also, the SCF/c-KIT system has been implicated in carcinogenesis of reproductive tissues due to its altered expression pattern or overactivation in consequence of gain-of-functions mutations. Over the years, it has also been shown that hormones, the primary regulators of reproductive function and causative agents in the case of hormone-dependent cancers, are also able to control the SCF/c-KIT tissue levels. Therefore, it is liable to suppose that disturbed SCF/c-KIT expression driven by (de)regulated hormone actions can be a relevant step towards carcinogenesis. The present review describes the SCF and c-KIT expression in cancers of reproductive tissues, discussing the implications of the hormonal regulation of the SCF/c-KIT system in cancer development. Understanding the relationship between hormonal imbalance and the SCF/c-KIT expression and activity would be relevant in the context of novel therapeutic approaches in reproductive cancers.