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Hormones-Dependent Cancers: New Aspects on Biochemistry and Molecular Pathology (II)

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 July 2019) | Viewed by 86625

Special Issue Editor

Special Issue Information

Dear Colleagues,

It is well-known that breast and prostate cancers are related to female and male hormones, respectively. Recently, it has been established that male steroid hormones, such as androgen, play an important role in female breast cancer progression. For approximately a dozen years, the possibility of anti-estrogen therapy for both female and male non-small lung carcinoma patients has been a significant area of research. In addition, the peptide hormones released by psychological stress directly stimulate growth signals in solid cancers, such as ovarian and endometrial cancers. Research into hormone-dependent cancers continues to progress at a rapid pace.

This Special Issue of the International Journal of Molecular Sciences entitled “Hormone-Dependent Cancers: New Aspects of Biochemistry and Molecular Pathology”, will focus on recent advances in hormone and cancer research, such as the molecular action of hormone receptors, biochemical analysis of steroid or peptide hormones, growth or invasive signals of hormone-related cancers, and mechanisms of resistance of endocrine therapy. Contributions on these related topics are welcome, including original research and reviews. We also very much welcome postdocs, PhD students, and young researchers. 

Dr. Yasuhiro Miki
Guest Editor

Manuscript Submission Information

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Keywords

  • hormone-related cancer
  • endocrine/intracrine
  • breast
  • prostate
  • endometrium
  • ovary
  • endocrine organs
  • female and male hormones
  • growth hormones
  • steroid hormones
  • peptide hormones
  • hormone receptors
  • biochemical analysis
  • pathophysiology
  • molecular biology

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Published Papers (15 papers)

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Editorial

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4 pages, 205 KiB  
Editorial
Hormone-Dependent Cancers: New Aspects on Biochemistry and Molecular Pathology
by Yasuhiro Miki
Int. J. Mol. Sci. 2023, 24(13), 10830; https://doi.org/10.3390/ijms241310830 - 29 Jun 2023
Viewed by 928
Abstract
Hormones, especially steroids, are closely involved in the physiological functions and proliferation of various target tissues and have long been known to play a key role in the tumorigenesis or carcinogenesis of these target tissues [...] Full article

Research

Jump to: Editorial, Review

16 pages, 1742 KiB  
Article
Systematic Identification of Characteristic Genes of Ovarian Clear Cell Carcinoma Compared with High-Grade Serous Carcinoma Based on RNA-Sequencing
by Saya Nagasawa, Kazuhiro Ikeda, Kuniko Horie-Inoue, Sho Sato, Atsuo Itakura, Satoru Takeda, Kosei Hasegawa and Satoshi Inoue
Int. J. Mol. Sci. 2019, 20(18), 4330; https://doi.org/10.3390/ijms20184330 - 04 Sep 2019
Cited by 18 | Viewed by 3194
Abstract
Objective: Ovarian cancer has the highest mortality among gynecological cancers. High-grade serous carcinoma (HGSC) is the most common histotype of ovarian cancer regardless of ethnicity, whereas clear cell carcinoma (CCC) is more common in East Asians than Caucasians. The elucidation of predominant signaling [...] Read more.
Objective: Ovarian cancer has the highest mortality among gynecological cancers. High-grade serous carcinoma (HGSC) is the most common histotype of ovarian cancer regardless of ethnicity, whereas clear cell carcinoma (CCC) is more common in East Asians than Caucasians. The elucidation of predominant signaling pathways in these cancers is the first step towards understanding their molecular mechanisms and developing their clinical management. Methods: RNA sequencing was performed for 27 clinical ovarian specimens from Japanese women. Principal component analysis (PCA) was conducted on the sequence data mapped on RefSeq with normalized read counts, and functional annotation analysis was performed on genes with substantial weights in PCA. Knockdown experiments were conducted on the selected genes on the basis of PCA. Results: Functional annotation analysis of PCA-defined genes showed predominant pathways, such as cell growth regulators and blood coagulators in CCC and transcription regulators in HGSC. Knockdown experiments showed that the inhibition of the calcium-dependent protein copine 8 (CPNE8) and the transcription factor basic helix-loop-helix family member e 41 (BHLHE41) repressed the proliferation of CCC- and HGSC-derived cells, respectively. Conclusions: This study identified CPNE8 and BHLHE41 as characteristic genes for CCC and HGSC, respectively. The systemic identification of differentially expressed genes in CCC and HGSC will provide useful information to understand transcriptomic differences in these ovarian cancers and to further develop potential diagnostic and therapeutic options for advanced disease. Full article
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15 pages, 2319 KiB  
Article
TUBB3 Reverses Resistance to Docetaxel and Cabazitaxel in Prostate Cancer
by Yohei Sekino, Xiangrui Han, Takafumi Kawaguchi, Takashi Babasaki, Keisuke Goto, Shogo Inoue, Tetsutaro Hayashi, Jun Teishima, Masaki Shiota, Wataru Yasui and Akio Matsubara
Int. J. Mol. Sci. 2019, 20(16), 3936; https://doi.org/10.3390/ijms20163936 - 13 Aug 2019
Cited by 41 | Viewed by 4287
Abstract
Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. [...] Read more.
Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment. Full article
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11 pages, 1952 KiB  
Article
F-Spondin Is the Signal by Which 2-Methoxyestradiol Induces Apoptosis in the Endometrial Cancer Cell Line Ishikawa
by Ramiro Rincón-Rodriguez, Dennise Mena, Javier Mena, Patricia Díaz-Saldivar, Emanuel Guajardo-Correa, Carlos Godoy-Guzman, Hugo Cardenas and Pedro A. Orihuela
Int. J. Mol. Sci. 2019, 20(16), 3850; https://doi.org/10.3390/ijms20163850 - 07 Aug 2019
Cited by 8 | Viewed by 3204
Abstract
The metabolite 2-methoxyestradiol (2ME) is an endogenous estrogen metabolite with potential therapeutic properties in reproductive cancers. However, the molecular mechanisms by which 2ME exerts its anticancer activity are not well elucidated. The purpose of this study was to determine the molecular signals associated [...] Read more.
The metabolite 2-methoxyestradiol (2ME) is an endogenous estrogen metabolite with potential therapeutic properties in reproductive cancers. However, the molecular mechanisms by which 2ME exerts its anticancer activity are not well elucidated. The purpose of this study was to determine the molecular signals associated with the apoptotic effects of 2ME in a human endometrial cancer cell line. Ishikawa cells were treated with non-apoptotic (0.1 µM) or apoptotic concentrations (5 µM) of 2ME, and 12 hours later mRNA levels for Scd2, Snx6, and Spon1 were determined by real-time PCR. We then investigated by immunofluorescence and Western blot the expression and distribution of F-spondin, encoded by Spon1, in Ishikawa cells treated with 2ME 5 µM at 6, 12, or 24 h after treatment. The role of estrogen receptors (ER) in the effect of 2ME on the Spon1 level was also investigated. Finally, we examined whether 2ME 5 µM induces cell death in Ishikawa cells pre-incubated with a neutralizing F-spondin antibody. Non-apoptotic or apoptotic concentrations of 2ME decreased Scd2 and increased Snx6. However, Spon1 was only increased with the 2ME apoptotic concentration. F-spondin protein was also increased at 12 and 24 h after 2ME treatment, while 2ME-induced Spon1 increase was independent of ER. Neutralization of F-spondin blocked the effect of 2ME on the cell viability. These results show that F-spondin signaling is one of the components in the apoptotic effects of 2ME on Ishikawa cells and provide experimental evidence underlying the mechanism of action of this estrogen metabolite on cancer cells. Full article
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12 pages, 232 KiB  
Article
Cadmium Exposure and Risk of Breast Cancer by Histological and Tumor Receptor Subtype in White Caucasian Women: A Hospital-Based Case-Control Study
by Loreta Strumylaite, Rima Kregzdyte, Algirdas Bogusevicius, Lina Poskiene, Dale Baranauskiene and Darius Pranys
Int. J. Mol. Sci. 2019, 20(12), 3029; https://doi.org/10.3390/ijms20123029 - 21 Jun 2019
Cited by 22 | Viewed by 2861
Abstract
As the majority of experimental studies suggest cadmium being metalloestrogen, we examined cadmium/breast cancer (BC) association by histological and tumor receptor subtype in 509 invasive BC patients and 1170 controls. Urinary cadmium was determined by atomic absorption spectrometry, and categorized using tertiles of [...] Read more.
As the majority of experimental studies suggest cadmium being metalloestrogen, we examined cadmium/breast cancer (BC) association by histological and tumor receptor subtype in 509 invasive BC patients and 1170 controls. Urinary cadmium was determined by atomic absorption spectrometry, and categorized using tertiles of its distribution in the controls: <0.18, 0.18–0.33, >0.33 kg × 10−9/kg × 10−3 creatinine. Relative to the lowest category of urinary cadmium adjusted odds ratio (OR) of ductal BC was 1.18 (95% confidence interval (CI): 0.89–1.58) in the intermediate and 1.53 (95% CI: 1.15–2.04) in the highest category. There was a significant association for hormone receptor-positive ductal BC: ORs per category increase were 1.34 (95% CI: 1.14–1.59) for estrogen receptor-positive (ER+), 1.33 (95% CI: 1.09–1.61) for progesterone receptor-positive (PR+) and 1.35 (95% CI: 1.11–1.65) for ER+/PR+ BC. We found a significant association between cadmium and human epidermal growth factor receptor 2-negative (HER2−) ductal BC. The strongest association with cadmium was for ER+/PR+/HER2− ductal BC. The associations between cadmium and lobular BC with hormone receptor-positive and HER2− were positive but insignificant. There was no evidence that the associations with cadmium differed for cancers with different tumor histology (p-heterogeneity > 0.05). This study provides evidence that urinary cadmium is associated with the risk of hormone receptor-positive and HER2− breast cancer independent of tumor histology. Full article
11 pages, 1474 KiB  
Article
Estrogen Receptor Positive Breast Cancer with High Expression of Androgen Receptor has Less Cytolytic Activity and Worse Response to Neoadjuvant Chemotherapy but Better Survival
by Maiko Okano, Masanori Oshi, Ali Linsk Butash, Mariko Asaoka, Eriko Katsuta, Xuan Peng, Qianya Qi, Li Yan and Kazuaki Takabe
Int. J. Mol. Sci. 2019, 20(11), 2655; https://doi.org/10.3390/ijms20112655 - 30 May 2019
Cited by 58 | Viewed by 4184
Abstract
Estrogen receptor (ER) positive breast cancer (BC), the most abundant BC subtype, is notorious for poor response to neoadjuvant chemotherapy (NAC). The androgen receptor (AR) was reported to support estradiol-mediated ER activity in an in vitro system. Recently, ER-positive BC with fewer tumor [...] Read more.
Estrogen receptor (ER) positive breast cancer (BC), the most abundant BC subtype, is notorious for poor response to neoadjuvant chemotherapy (NAC). The androgen receptor (AR) was reported to support estradiol-mediated ER activity in an in vitro system. Recently, ER-positive BC with fewer tumor infiltrating lymphocytes (TILs) was shown to have a better prognosis, opposite to the trend seen with ER-negative BC. We hypothesized that ER-positive BC with high expression of AR will have fewer TILs and an inferior response to NAC, but with a better prognosis. In both TCGA and METABRIC cohorts, AR expression was significantly higher in ER-positive BCs compared to ER-negatives (p < 0.001, p < 0.001, respectively) and it correlated with ER expression (R = 0.630, R = 0.509, respectively). In ER-positive tumors, AR high tumors enriched UV response down (NES = 2.01, p < 0.001), and AR low tumors enriched DNA repair (NES = −2.02, p < 0.001). AR high tumors were significantly associated with procancer regulatory T-cells, and AR low tumors were associated with anticancer immune cells, such as CD4, CD8, and Gamma-Delta T-cells and memory B-cells in ER-positive BC (p < 0.01). Further, cytolytic activity was significantly lower in AR high BC in both cohorts. Finally, AR high tumors had a significantly lower rate of attaining pathological complete response to NAC (GSE22358), but better survival. In conclusion, our results demonstrated that high AR has fewer tumor infiltrating lymphocytes as well as cytolytic activity and an inferior response to NAC, but better survival in ER-positive BC. Full article
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15 pages, 5145 KiB  
Article
Core-Fucosylated Tetra-Antennary N-Glycan Containing A Single N-Acetyllactosamine Branch Is Associated with Poor Survival Outcome in Breast Cancer
by Harmin Herrera, Tinslee Dilday, Allison Uber, Danielle Scott, Joelle N. Zambrano, Mengjun Wang, Peggi M. Angel, Anand S. Mehta, Richard R. Drake, Elizabeth G. Hill and Elizabeth S. Yeh
Int. J. Mol. Sci. 2019, 20(10), 2528; https://doi.org/10.3390/ijms20102528 - 23 May 2019
Cited by 32 | Viewed by 4309
Abstract
(1) Glycoproteins account for ~80% of proteins located at the cell surface and in the extracellular matrix. A growing body of evidence indicates that α-L-fucose protein modifications contribute to breast cancer progression and metastatic disease. (2) Using a combination of techniques, including matrix-assisted [...] Read more.
(1) Glycoproteins account for ~80% of proteins located at the cell surface and in the extracellular matrix. A growing body of evidence indicates that α-L-fucose protein modifications contribute to breast cancer progression and metastatic disease. (2) Using a combination of techniques, including matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) based in cell and on tissue imaging and glycan sequencing using exoglycosidase analysis coupled to hydrophilic interaction ultra-high performance liquid chromatography (HILIC UPLC), we establish that a core-fucosylated tetra-antennary glycan containing a single N-acetyllactosamine (F(6)A4G4Lac1) is associated with poor clinical outcomes in breast cancer, including lymph node metastasis, recurrent disease, and reduced survival. (3) This study is the first to identify a single N-glycan, F(6)A4G4Lac1, as having a correlation with poor clinical outcomes in breast cancer. Full article
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22 pages, 4454 KiB  
Article
The polypeptide GALNT6 Displays Redundant Functions upon Suppression of its Closest Homolog GALNT3 in Mediating Aberrant O-Glycosylation, Associated with Ovarian Cancer Progression
by Razan Sheta, Magdalena Bachvarova, Elizabeth Macdonald, Stephane Gobeil, Barbara Vanderhyden and Dimcho Bachvarov
Int. J. Mol. Sci. 2019, 20(9), 2264; https://doi.org/10.3390/ijms20092264 - 08 May 2019
Cited by 16 | Viewed by 4773
Abstract
Epithelial ovarian cancer (EOC) represents the most lethal gynecologic malignancy; a better understanding of the molecular mechanisms associated with EOC etiology could substantially improve EOC management. Aberrant O-glycosylation in cancer is attributed to alteration of N-acetylgalactosaminyltransferases (GalNAc-Ts). Reports suggest a genetic and functional [...] Read more.
Epithelial ovarian cancer (EOC) represents the most lethal gynecologic malignancy; a better understanding of the molecular mechanisms associated with EOC etiology could substantially improve EOC management. Aberrant O-glycosylation in cancer is attributed to alteration of N-acetylgalactosaminyltransferases (GalNAc-Ts). Reports suggest a genetic and functional redundancy between GalNAc-Ts, and our previous data are indicative of an induction of GALNT6 expression upon GALNT3 suppression in EOC cells. We performed single GALNT3 and double GALNT3/T6 suppression in EOC cells, using a combination of the CRISPR-Cas9 system and shRNA-mediated gene silencing. The effect of single GALNT3 and double GALNT3/T6 inhibition was monitored both in vitro (on EOC cells roliferation, migration, and invasion) and in vivo (on tumor formation and survival of experimental animals). We confirmed that GALNT3 gene ablation leads to strong and rather compensatory GALNT6 upregulation in EOC cells. Moreover, double GALNT3/T6 suppression was significantly associated with stronger inhibitory effects on EOC cell proliferation, migration, and invasion, and accordingly displayed a significant increase in animal survival rates compared with GALNT3-ablated and control (Ctrl) EOC cells. Our data suggest a possible functional redundancy of GalNAc-Ts (GALNT3 and T6) in EOC, with the perspective of using both these enzymes as novel EOC biomarkers and/or therapeutic targets. Full article
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16 pages, 6300 KiB  
Article
Clinical and Biological Significance of ESR1 Gene Alteration and Estrogen Receptors Isoforms Expression in Breast Cancer Patients
by Anna Nagel, Jolanta Szade, Mariola Iliszko, Julia Elzanowska, Marzena Welnicka-Jaskiewicz, Jaroslaw Skokowski, Grzegorz Stasilojc, Jacek Bigda, Rafal Sadej, Anna Zaczek and Aleksandra Markiewicz
Int. J. Mol. Sci. 2019, 20(8), 1881; https://doi.org/10.3390/ijms20081881 - 16 Apr 2019
Cited by 8 | Viewed by 3467
Abstract
The amplification of estrogen receptor alpha (ERα) encoded by the ESR1 gene has been described as having a prognostic role in breast cancer patients. However, increased dosage of the ESR1 gene (tested by real-time PCR) is also observed in ER-negative breast cancers, which [...] Read more.
The amplification of estrogen receptor alpha (ERα) encoded by the ESR1 gene has been described as having a prognostic role in breast cancer patients. However, increased dosage of the ESR1 gene (tested by real-time PCR) is also observed in ER-negative breast cancers, which might suggest the expression of alternative isoforms of ERα (other than classical ERα of 66 kDa). In the current work, we have investigated the ESR1 gene dosage in 402 primary breast cancer patients as well as the expression of ERα isoforms—ERα66 and ERα36—on mRNA and protein levels. The obtained results were correlated with clinicopathological data of the patients. Results showed that increased ESR1 gene dosage is not related to ESR1 gene amplification measured by fluorescent in situ hybridization (FISH), but it correlates with the decreased expression of ERα66 isoform (p = 0.01). Interestingly, the short ER isoform ERα36 was expressed in samples with increased ESR1 gene dosage, suggesting that genomic aberration might influence the expression of that particular isoform. Similarly to ESR1 increased gene dosage, high ERα36 expression was linked with the decreased disease-free survival of the patients (p = 0.05), which was independent of the status of the classical ERα66 level in breast tumors. Full article
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12 pages, 7651 KiB  
Article
Concomitant Expression of Prolactin Receptor and TGFβ Receptors in Breast Cancer: Association with Less Aggressive Phenotype and Favorable Patient Outcome
by Ibrahim Y. Hachim, Vanessa M. López-Ozuna, Mahmood Y. Hachim, Jean-Jacques Lebrun and Suhad Ali
Int. J. Mol. Sci. 2019, 20(7), 1640; https://doi.org/10.3390/ijms20071640 - 02 Apr 2019
Cited by 7 | Viewed by 3128
Abstract
The epithelial–mesenchymal transition (EMT) process is known to play an essential role in tumor progression, metastasis and resistance to therapy. This report evaluated the prognostic value of co-expression of the receptor for prolactin (PRLR), a suppressor of EMT, and the receptors for transforming [...] Read more.
The epithelial–mesenchymal transition (EMT) process is known to play an essential role in tumor progression, metastasis and resistance to therapy. This report evaluated the prognostic value of co-expression of the receptor for prolactin (PRLR), a suppressor of EMT, and the receptors for transforming growth factor β (TGFβRI and TGFβRII), an inducer of EMT, in association with different clinicopathological parameters using TMA of 102 breast cancer patients and publicly available data on breast cancer patients. Interestingly, the results revealed that malignant tissues had significantly lower levels of concomitant protein expression of these receptors in comparison to normal/benign breast tissue. In addition, a higher level of concomitant expression was also observed in less aggressive breast cancer phenotypes, including low grade tumors, luminal breast cancer subtype, and less advanced stages of the disease (lymph node negative and early stages). Moreover, the results also showed that the expression of a gene signature composed of PRLR/TGFβRI/TGFβRII correlates more with differentiated grade I tumors, and identified a subset of patients showing better survival outcomes evident in luminal B and HER-2 enriched molecular subtypes. Together, these results indicate that loss of the co-expression of PRLR, TGFβRI and TGFβRII is indicative of aggressiveness and poor patient survival outcomes in breast cancer. Full article
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14 pages, 3879 KiB  
Article
Comprehensive Genomic Profiling of Androgen-Receptor-Negative Canine Prostate Cancer
by Renée Laufer-Amorim, Carlos Eduardo Fonseca-Alves, Rolando Andre Rios Villacis, Sandra Aparecida Drigo Linde, Marcio Carvalho, Simon Jonas Larsen, Fabio Albuquerque Marchi and Silvia Regina Rogatto
Int. J. Mol. Sci. 2019, 20(7), 1555; https://doi.org/10.3390/ijms20071555 - 28 Mar 2019
Cited by 19 | Viewed by 4050
Abstract
Canine carcinomas have been considered natural models for human diseases; however, the genomic profile of canine prostate cancers (PCs) has not been explored. In this study, 14 PC androgen-receptor-negative cases, 4 proliferative inflammatory atrophies (PIA), and 5 normal prostate tissues were investigated by [...] Read more.
Canine carcinomas have been considered natural models for human diseases; however, the genomic profile of canine prostate cancers (PCs) has not been explored. In this study, 14 PC androgen-receptor-negative cases, 4 proliferative inflammatory atrophies (PIA), and 5 normal prostate tissues were investigated by array-based comparative genomic hybridization (aCGH). Copy number alterations (CNAs) were assessed using the Canine Genome CGH Microarray 4 × 44K (Agilent Technologies). Genes covered by recurrent CNAs were submitted to enrichment and cross-validation analysis. In addition, the expression levels of TP53, MDM2 and ZBTB4 were evaluated in an independent set of cases by qPCR. PC cases presented genomic complexity, while PIA samples had a small number of CNAs. Recurrent losses covering well-known tumor suppressor genes, such as ATM, BRCA1, CDH1, MEN1 and TP53, were found in PC. The in silico functional analysis showed several cancer-related genes associated with canonical pathways and interaction networks previously described in human PC. The MDM2, TP53, and ZBTB4 copy number alterations were translated into altered expression levels. A cross-validation analysis using The Cancer Genome Atlas (TCGA) database for human PC uncovered similarities between canine and human PCs. Androgen-receptor-negative canine PC is a complex disease characterized by high genomic instability, showing a set of genes with similar alterations to human cancer. Full article
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13 pages, 2366 KiB  
Article
Obesity-Altered Adipose Stem Cells Promote ER+ Breast Cancer Metastasis through Estrogen Independent Pathways
by Rachel A. Sabol, Adam Beighley, Paulina Giacomelli, Rachel M. Wise, Mark A. A. Harrison, Ben A. O’Donnnell, Brianne N. Sullivan, Jacob D. Lampenfeld, Margarite D. Matossian, Melyssa R. Bratton, Guangdi Wang, Bridgette M. Collins-Burow, Matthew E. Burow and Bruce A. Bunnell
Int. J. Mol. Sci. 2019, 20(6), 1419; https://doi.org/10.3390/ijms20061419 - 20 Mar 2019
Cited by 22 | Viewed by 3747
Abstract
Adipose stem cells (ASCs) play an essential role in tumor microenvironments. These cells are altered by obesity (obASCs) and previous studies have shown that obASCs secrete higher levels of leptin. Increased leptin, which upregulates estrogen receptor alpha (ERα) and aromatase, enhances estrogen bioavailability [...] Read more.
Adipose stem cells (ASCs) play an essential role in tumor microenvironments. These cells are altered by obesity (obASCs) and previous studies have shown that obASCs secrete higher levels of leptin. Increased leptin, which upregulates estrogen receptor alpha (ERα) and aromatase, enhances estrogen bioavailability and signaling in estrogen receptor positive (ER+) breast cancer (BC) tumor growth and metastasis. In this study, we evaluate the effect of obASCs on ER+BC outside of the ERα signaling axis using breast cancer models with constitutively active ERα resulting from clinically relevant mutations (Y537S and D538G). We found that while obASCs promote tumor growth and proliferation, it occurs mostly through abrogated estrogen signaling when BC has constitutive ER activity. However, obASCs have a similar promotion of metastasis irrespective of ER status, demonstrating that obASC promotion of metastasis may not be completely estrogen dependent. We found that obASCs upregulate two genes in both ER wild type (WT) and ER mutant (MUT) BC: SERPINE1 and ABCB1. This study demonstrates that obASCs promote metastasis in ER WT and MUT xenografts and an ER MUT patient derived xenograft (PDX) model. However, obASCs promote tumor growth only in ER WT xenografts. Full article
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Review

Jump to: Editorial, Research

16 pages, 432 KiB  
Review
Lipid Metabolism and Endocrine Resistance in Prostate Cancer, and New Opportunities for Therapy
by Gergana E. Stoykova and Isabel R. Schlaepfer
Int. J. Mol. Sci. 2019, 20(11), 2626; https://doi.org/10.3390/ijms20112626 - 28 May 2019
Cited by 77 | Viewed by 10204
Abstract
Prostate cancer (PCa) is the most common cancer in men, and more than 10% of men will be diagnosed with PCa during their lifetime. Patients that are not cured with surgery or radiation are largely treated with endocrine therapies that target androgens or [...] Read more.
Prostate cancer (PCa) is the most common cancer in men, and more than 10% of men will be diagnosed with PCa during their lifetime. Patients that are not cured with surgery or radiation are largely treated with endocrine therapies that target androgens or the androgen receptor (AR), a major driver of PCa. In response to androgen deprivation, most PCas progress to castrate resistant PCa, which is treated with anti-androgens like enzalutamide, but tumors still progress and become incurable. Thus, there is a critical need to identify cellular pathways that allow tumors to escape anti-androgen therapies. Epidemiological studies suggest that high-fat diets play important roles in PCa progression. Lipid metabolism rewires the PCa metabolome to support growth and resistance to endocrine therapies, although the exact mechanisms remain obscure. Therapeutic effects have been observed inhibiting several aspects of PCa lipid metabolism: Synthesis, uptake, and oxidation. Since AR remains a driver of PCa in advanced disease, strategies targeting both lipid metabolism and AR are starting to emerge, providing new opportunities to re-sensitize tumors to endocrine therapies with lipid metabolic approaches. Full article
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16 pages, 1242 KiB  
Review
Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer
by Namrata Khurana and Suresh C. Sikka
Int. J. Mol. Sci. 2019, 20(9), 2066; https://doi.org/10.3390/ijms20092066 - 26 Apr 2019
Cited by 41 | Viewed by 8301
Abstract
Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the [...] Read more.
Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa. Full article
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21 pages, 1194 KiB  
Review
Future Aspects for Cannabinoids in Breast Cancer Therapy
by Terézia Kisková, Felicitas Mungenast, Mária Suváková, Walter Jäger and Theresia Thalhammer
Int. J. Mol. Sci. 2019, 20(7), 1673; https://doi.org/10.3390/ijms20071673 - 03 Apr 2019
Cited by 82 | Viewed by 25085
Abstract
Cannabinoids (CBs) from Cannabis sativa provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients. Additionally, they may decelerate tumor progression in breast cancer patients. Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other [...] Read more.
Cannabinoids (CBs) from Cannabis sativa provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients. Additionally, they may decelerate tumor progression in breast cancer patients. Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other CBs inhibited disease progression in breast cancer models. The effects of CBs on signaling pathways in cancer cells are conferred via G-protein coupled CB-receptors (CB-Rs), CB1-R and CB2-R, but also via other receptors, and in a receptor-independent way. THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both. In breast cancer, CB1-R expression is moderate, but CB2-R expression is high, which is related to tumor aggressiveness. CBs block cell cycle progression and cell growth and induce cancer cell apoptosis by inhibiting constitutive active pro-oncogenic signaling pathways, such as the extracellular-signal-regulated kinase pathway. They reduce angiogenesis and tumor metastasis in animal breast cancer models. CBs are not only active against estrogen receptor-positive, but also against estrogen-resistant breast cancer cells. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B- and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis. Furthermore, selective estrogen receptor modulators (SERMs), including tamoxifen, bind to CB-Rs; this process may contribute to the growth inhibitory effect of SERMs in cancer cells lacking the estrogen receptor. In summary, CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression. Full article
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