Cancers

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6 pages, 1049 KiB

Open AccessEditorial

New Insights into Breast and Endometrial Cancers

by Yasuhiro Miki

Cancers 2020, 12(9), 2595; https://doi.org/10.3390/cancers12092595 - 11 Sep 2020

Cited by 6 | Viewed by 2524

Abstract

Cancers of the breast and endometrium are some of the most common cancers affecting women [...] Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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Research

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14 pages, 2240 KiB

Open AccessArticle

Baseline Serum HE4 But Not Tissue HE4 Expression Predicts Response to the Levonorgestrel-Releasing Intrauterine System in Atypical Hyperplasia and Early Stage Endometrial Cancer

by Roya Behrouzi, Neil A. J. Ryan, Chloe E. Barr, Abigail E. Derbyshire, Y. Louise Wan, Zoe Maskell, Katie Stocking, Philip W. Pemberton, James Bolton, Rhona J. McVey and Emma J. Crosbie

Cancers 2020, 12(2), 276; https://doi.org/10.3390/cancers12020276 - 23 Jan 2020

Cited by 19 | Viewed by 3368

Abstract

The levonorgestrel-releasing intrauterine system (LNG-IUS) is a conservative management option for atypical hyperplasia (AH) and low grade early stage endometrial cancer (EEC), but around 1 in 3 patients fail to respond to treatment. The aim of this study was to investigate if serum [...] Read more.

The levonorgestrel-releasing intrauterine system (LNG-IUS) is a conservative management option for atypical hyperplasia (AH) and low grade early stage endometrial cancer (EEC), but around 1 in 3 patients fail to respond to treatment. The aim of this study was to investigate if serum and/or tissue HE4 expression could predict response to LNG-IUS therapy. Patients with AH or presumed Stage I EEC had serum and endometrial samples taken at baseline and at 3-month intervals over 12 months post-insertion of LNG-IUS. 74 patients were recruited and baseline demographics recorded. Of 57 patients for whom response was histologically determinable, 39 (68%) were responders and 18 (32%) non-responders. Mean baseline serum HE4 was significantly lower in responders (62.1 ± 1.1 pM, 95% confidence interval (CI) 52.7–73.2), compared to non-responders (125.6 ± 1.3 pM, 95% CI 74.5–211.7, p = 0.014), including when considering age, BMI, menopausal status, smoking status, and histological grade as covariables (p = 0.005). Baseline tissue HE4 expression was not significantly different in responders compared to non-responders (p = 0.999). Responders showed a significant mean reduction (−9.8 ± 3.4%, 95% CI −16.7 to −2.8%, p = 0.008) in serum HE4 between baseline and 3 months (p = 0.008), whereas non-responders showed no significant change (p = 0.676). Neither responders nor non-responders showed a significant percentage change in serum HE4 from baseline beyond 3 months (p > 0.05). Change in serum HE4 between baseline and 3 and 6 months and tissue HE4 tissue expression between baseline and 3, 6, and 12 months was not significantly different in responders compared to non-responders (p > 0.05). This study suggests that baseline serum HE4, but not baseline tissue HE4 expression, is independently predictive of response to the LNG-IUS and could be used to guide management decisions. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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12 pages, 1770 KiB

Open AccessArticle

NF-kappa B Signaling-Related Signatures Are Connected with the Mesenchymal Phenotype of Circulating Tumor Cells in Non-Metastatic Breast Cancer

by Marta Popeda, Tomasz Stokowy, Natalia Bednarz-Knoll, Anna Jurek, Magdalena Niemira, Agnieszka Bielska, Adam Kretowski, Leszek Kalinowski, Jolanta Szade, Aleksandra Markiewicz and Anna J. Zaczek

Cancers 2019, 11(12), 1961; https://doi.org/10.3390/cancers11121961 - 6 Dec 2019

Cited by 18 | Viewed by 4252

Abstract

The role of circulating tumor cells (CTCs), tumor microenvironment (TME), and the immune system in the formation of metastasis is evident, yet the details of their interactions remain unknown. This study aimed at exploring the immunotranscriptome of primary tumors associated with the status [...] Read more.

The role of circulating tumor cells (CTCs), tumor microenvironment (TME), and the immune system in the formation of metastasis is evident, yet the details of their interactions remain unknown. This study aimed at exploring the immunotranscriptome of primary tumors associated with the status of CTCs in breast cancer (BCa) patients. The expression of 730 immune-related genes in formalin-fixed paraffin-embedded samples was analyzed using the multigenomic NanoString technology and correlated with the presence and the phenotype of CTCs. Upregulation of 37 genes and downregulation of 1 gene were observed in patients characterized by a mesenchymal phenotype of CTCs when compared to patients with epithelial CTCs. The upregulated genes were involved in NF-kappa B signaling and in the production of type I interferons. The clinical significance of the differentially expressed genes was evaluated using The Cancer Genome Atlas (TCGA) data of a breast invasive carcinoma (BRCA) cohort. Five of the upregulated genes—PSMD7, C2, IFNAR1, CD84, and CYLD—were independent prognostic factors in terms of overall and disease-free survival. To conclude, our data identify a group of genes that are upregulated in BCa patients with mesenchymal CTCs and reveal their prognostic potential, thus indicating that they merit further investigation. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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17 pages, 4009 KiB

Open AccessArticle

Anti-Tumor Effect of Inhibition of DNA Damage Response Proteins, ATM and ATR, in Endometrial Cancer Cells

by Makoto Takeuchi, Michihiro Tanikawa, Kazunori Nagasaka, Katsutoshi Oda, Yoshiko Kawata, Shinya Oki, Chuwa Agapiti, Kenbun Sone, Yuko Miyagawa, Haruko Hiraike, Osamu Wada-Hiraike, Hiroyuki Kuramoto, Takuya Ayabe, Yutaka Osuga and Tomoyuki Fujii

Cancers 2019, 11(12), 1913; https://doi.org/10.3390/cancers11121913 - 1 Dec 2019

Cited by 23 | Viewed by 4494

Abstract

While the incidence of endometrial cancer continues to rise, the therapeutic options remain limited for advanced or recurrent cases, and most cases are resistant to therapy. The anti-tumor effect of many chemotherapeutic drugs and radiotherapy depends on the induction of DNA damage in [...] Read more.

While the incidence of endometrial cancer continues to rise, the therapeutic options remain limited for advanced or recurrent cases, and most cases are resistant to therapy. The anti-tumor effect of many chemotherapeutic drugs and radiotherapy depends on the induction of DNA damage in cancer cells; thus, activation of DNA damage response (DDR) pathways is considered an important factor affecting resistance to therapy. When some DDR pathways are inactivated, inhibition of other DDR pathways can induce cancer-specific synthetic lethality. Therefore, DDR pathways are considered as promising candidates for molecular-targeted therapy for cancer. The crosstalking ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 1 (ATR-Chk1) and ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 2 (ATM-Chk2) pathways are the main pathways of DNA damage response. In this study, we investigated the anti-tumor effect of inhibitors of these pathways in vitro by assessing the effect of the combination of ATM or ATR inhibitors and conventional DNA-damaging therapy (doxorubicin (DXR), cisplatin (CDDP), and irradiation) on endometrial cancer cells. Both the inhibitors enhanced the sensitivity of cells to DXR, CDDP, and irradiation. Moreover, the combination of ATR and Chk1 inhibitors induced DNA damage in endometrial cancer cells and inhibited cell proliferation synergistically. Therefore, these molecular therapies targeting DNA damage response pathways are promising new treatment strategies for endometrial cancer. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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21 pages, 4251 KiB

Open AccessArticle

Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated Fibroblasts and Enhances Breast Tumor Progression

by Stefania Catalano, Salvatore Panza, Giuseppina Augimeri, Cinzia Giordano, Rocco Malivindi, Luca Gelsomino, Stefania Marsico, Francesca Giordano, Balázs Győrffy, Daniela Bonofiglio, Sebastiano Andò and Ines Barone

Cancers 2019, 11(11), 1740; https://doi.org/10.3390/cancers11111740 - 6 Nov 2019

Cited by 30 | Viewed by 4107

Abstract

The overexpression of phosphodiesterase (PDE) 5 is frequently found in various human cancers, such as those of the breast. However, PDE5’s role in the tumor microenvironment is still unknown. As PDE5 represents a high-value therapeutic target, we investigated whether the expression and function [...] Read more.

The overexpression of phosphodiesterase (PDE) 5 is frequently found in various human cancers, such as those of the breast. However, PDE5’s role in the tumor microenvironment is still unknown. As PDE5 represents a high-value therapeutic target, we investigated whether the expression and function of PDE5 in breast cancer-associated fibroblasts (CAFs) may be clinically relevant to malignant progression. PDE5 expression was increased in human breast cancer stroma compared with normal stroma and was correlated to a shorter overall survival. Treatment of CAFs, isolated from breast tumor biopsies, with selective PDE5 inhibitors inhibited their proliferation, motility, and invasiveness, and negatively controlled tumor–stroma interactions in both ‘in vitro’ and ‘in vivo’ models. PDE5 stable overexpression transformed immortalized mouse embryonic fibroblasts (MEFs) towards an activated fibroblast phenotype, impacting their intrinsic characteristics and paracrine effects on breast cancer cell growth and migration through an enhanced production of the C-X-C motif chemokine 16 (CXCL16). On the other hand, CAF exposure to PDE5 inhibitors was associated with reduced CXCL16 expression and secretion. Importantly, CXCL16 levels in breast cancer stroma showed a strong correlation with PDE5 levels and poor patient outcomes. In conclusion, PDE5 is overexpressed in breast cancer stroma, enhances the tumor-stimulatory activities of fibroblasts, and impacts clinical outcomes; thus, we propose this enzyme as an attractive candidate for prognosis and a potential target for treatments in breast cancer patients. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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22 pages, 3877 KiB

Open AccessArticle

Synergistic Antitumorigenic Activity of Calcitriol with Curcumin or Resveratrol is Mediated by Angiogenesis Inhibition in Triple Negative Breast Cancer Xenografts

by Janice García-Quiroz, Rocío García-Becerra, Clara Santos-Cuevas, Gerardo J. Ramírez-Nava, Gabriela Morales-Guadarrama, Nohemí Cárdenas-Ochoa, Mariana Segovia-Mendoza, Heriberto Prado-Garcia, David Ordaz-Rosado, Euclides Avila, Andrea Olmos-Ortiz, Sofía López-Cisneros, Fernando Larrea and Lorenza Díaz

Cancers 2019, 11(11), 1739; https://doi.org/10.3390/cancers11111739 - 6 Nov 2019

Cited by 49 | Viewed by 4670

Abstract

Calcitriol is a multitarget anticancer hormone; however, its effects on angiogenesis remain contradictory. Herein, we tested whether the antiangiogenic phytochemicals curcumin or resveratrol improved calcitriol antitumorigenic effects in vivo. Triple-negative breast cancer tumoral cells (MBCDF-T) were xenografted in nude mice, maintaining treatments for [...] Read more.

Calcitriol is a multitarget anticancer hormone; however, its effects on angiogenesis remain contradictory. Herein, we tested whether the antiangiogenic phytochemicals curcumin or resveratrol improved calcitriol antitumorigenic effects in vivo. Triple-negative breast cancer tumoral cells (MBCDF-T) were xenografted in nude mice, maintaining treatments for 3 weeks. Tumor onset, volume and microvessel density were significantly reduced in mice coadministered with calcitriol and curcumin (Cal+Cur). Vessel count was also reduced in mice simultaneously treated with calcitriol and resveratrol (Cal+Rsv). Cal+Cur and Cal+Rsv treatments resulted in less tumor activated endothelium, as demonstrated by decreased tumor uptake of integrin-targeted biosensors in vivo. The renal gene expression of Cyp24a1 and Cyp27b1 suggested increased calcitriol bioactivity in the combined regimens. In vitro, the phytochemicals inhibited both MBCDF-T and endothelial cells proliferation, while potentiated calcitriol’s ability to reduce MBCDF-T cell-growth and endothelial cells migration. Resveratrol induced endothelial cell death, as deduced by increased sub-G1 cells accumulation, explaining the reduced tumor vessel number in resveratrol-treated mice, which further diminished when combined with calcitriol. In conclusion, the concomitant administration of calcitriol with curcumin or resveratrol synergistically promoted anticancer effects in vitro and in vivo in human mammary tumor cells. Whereas the results suggest different mechanisms of action of the phytochemicals when coadministered with calcitriol, the converging biological effect was inhibition of tumor neoangiogenesis. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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14 pages, 1835 KiB

Open AccessArticle

17β-Estradiol Activates HSF1 via MAPK Signaling in ERα-Positive Breast Cancer Cells

by Natalia Vydra, Patryk Janus, Agnieszka Toma-Jonik, Tomasz Stokowy, Katarzyna Mrowiec, Joanna Korfanty, Anna Długajczyk, Bartosz Wojtaś, Bartłomiej Gielniewski and Wiesława Widłak

Cancers 2019, 11(10), 1533; https://doi.org/10.3390/cancers11101533 - 11 Oct 2019

Cited by 22 | Viewed by 4085

Abstract

Heat Shock Factor 1 (HSF1) is a key regulator of gene expression during acute environmental stress that enables the cell survival, which is also involved in different cancer-related processes. A high level of HSF1 in estrogen receptor (ER)-positive breast cancer patients correlated with [...] Read more.

Heat Shock Factor 1 (HSF1) is a key regulator of gene expression during acute environmental stress that enables the cell survival, which is also involved in different cancer-related processes. A high level of HSF1 in estrogen receptor (ER)-positive breast cancer patients correlated with a worse prognosis. Here we demonstrated that 17β-estradiol (E2), as well as xenoestrogen bisphenol A and ERα agonist propyl pyrazole triol, led to HSF1 phosphorylation on S326 in ERα positive but not in ERα-negative mammary breast cancer cells. Furthermore, we showed that MAPK signaling (via MEK1/2) but not mTOR signaling was involved in E2/ERα-dependent activation of HSF1. E2activated HSF1 was transcriptionally potent and several genes essential for breast cancer cells growth and/or ERα action, including HSPB8, LHX4, PRKCE, WWC1, and GREB1, were activated by E2 in a HSF1-dependent manner. Our findings suggest a hypothetical positive feedback loop between E2/ERα and HSF1 signaling, which may support the growth of estrogen-dependent tumors. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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14 pages, 620 KiB

Open AccessArticle

Analysis of Promoter-Associated Chromatin Interactions Reveals Biologically Relevant Candidate Target Genes at Endometrial Cancer Risk Loci

by Tracy A. O’Mara, Amanda B. Spurdle, Dylan M. Glubb and Endometrial Cancer Association Consortium

Cancers 2019, 11(10), 1440; https://doi.org/10.3390/cancers11101440 - 26 Sep 2019

Cited by 22 | Viewed by 4800

Abstract

The identification of target genes at genome-wide association study (GWAS) loci is a major obstacle for GWAS follow-up. To identify candidate target genes at the 16 known endometrial cancer GWAS risk loci, we performed HiChIP chromatin looping analysis of endometrial cell lines. To [...] Read more.

The identification of target genes at genome-wide association study (GWAS) loci is a major obstacle for GWAS follow-up. To identify candidate target genes at the 16 known endometrial cancer GWAS risk loci, we performed HiChIP chromatin looping analysis of endometrial cell lines. To enrich for enhancer–promoter interactions, a mechanism through which GWAS variation may target genes, we captured chromatin loops associated with H3K27Ac histone, characteristic of promoters and enhancers. Analysis of HiChIP loops contacting promoters revealed enrichment for endometrial cancer GWAS heritability and intersection with endometrial cancer risk variation identified 103 HiChIP target genes at 13 risk loci. Expression of four HiChIP target genes (SNX11, SRP14, HOXB2 and BCL11A) was associated with risk variation, providing further evidence for their targeting. Network analysis functionally prioritized a set of proteins that interact with those encoded by HiChIP target genes, and this set was enriched for pan-cancer and endometrial cancer drivers. Lastly, HiChIP target genes and prioritized interacting proteins were over-represented in pathways related to endometrial cancer development. In summary, we have generated the first global chromatin looping data from normal and tumoral endometrial cells, enabling analysis of all known endometrial cancer risk loci and identifying biologically relevant candidate target genes. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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17 pages, 2025 KiB

Open AccessArticle

Should Tumor Infiltrating Lymphocytes, Androgen Receptor, and FOXA1 Expression Predict the Clinical Outcome in Triple Negative Breast Cancer Patients?

by Anita Mangia, Concetta Saponaro, Alessandro Vagheggini, Giuseppina Opinto, Matteo Centonze, Chiara Vicenti, Ondina Popescu, Maria Pastena, Francesco Giotta and Nicola Silvestris

Cancers 2019, 11(9), 1393; https://doi.org/10.3390/cancers11091393 - 18 Sep 2019

Cited by 13 | Viewed by 4617

Abstract

Tumor-infiltrating lymphocytes (TILs) are a valuable indicator of the immune microenvironment that plays the central role in new anticancer drugs. TILs have a strong prognostic role in triple negative breast cancer (TNBC). Little is known about the interaction with the androgen receptor (AR) [...] Read more.

Tumor-infiltrating lymphocytes (TILs) are a valuable indicator of the immune microenvironment that plays the central role in new anticancer drugs. TILs have a strong prognostic role in triple negative breast cancer (TNBC). Little is known about the interaction with the androgen receptor (AR) and forkhead box A1 (FOXA1). We analyzed the relationships between TIL levels, AR, and FOXA1 expression and their clinical significance in TNBC patients. Further, we investigated their interaction with other biomarkers like programmed cell death ligand-1 (PD-L1), breast cancer type 1 susceptibility protein (BRCA1), poly (ADP-Ribose) polymerase 1 (PARP1), and Na+/H+ exchanger regulatory factor 1 (NHERF1). The expression of the proteins was evaluated by immunohistochemistry in 124 TNBC samples. TILs were performed adhering to International TILs Working Group 2014 criteria. Cox proportional hazards models were also used to identify risk factors associated with poor prognosis. Multivariate analysis identified TILs as independent prognostic factor of disease free survival (DFS; p = 0.045). A Kaplan–Meyer analysis revealed that the patients with high TILs had a better DFS compared to patients with low TILs (p = 0.037), and the phenotypes TILs−/AR+ and TILs−/FOXA1− had a worse DFS (p = 0.032, p = 0.001 respectively). AR was associated with FOXA1 expression (p = 0.007), and the tumors FOXA1+ presented low levels of TILs (p = 0.028). A poor DFS was observed for AR+/FOXA1+ tumors compared to other TNBCs (p = 0.0117). Low TILs score was associated with poor patients’ survival, and TILs level in combination with AR or FOXA1 expression affected patient’s clinical outcome. In addition, AR+/FOXA1+ phenotype identified a specific subgroup of TNBC patients with poor prognosis. These data may suggest new ways of therapeutic intervention to support current treatments. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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19 pages, 1633 KiB

Open AccessArticle

A Tyrosine Kinase Expression Signature Predicts the Post-Operative Clinical Outcome in Triple Negative Breast Cancers

by Alexandre de Nonneville, Pascal Finetti, José Adelaide, Éric Lambaudie, Patrice Viens, Anthony Gonçalves, Daniel Birnbaum, Emilie Mamessier and François Bertucci

Cancers 2019, 11(8), 1158; https://doi.org/10.3390/cancers11081158 - 13 Aug 2019

Cited by 8 | Viewed by 3325

Abstract

Triple negative breast cancer (TNBC) represent 15% of breast cancers. Histoclinical features and marketed prognostic gene expression signatures (GES) failed to identify good- and poor-prognosis patients. Tyrosine kinases (TK) represent potential prognostic and/or therapeutic targets for TNBC. We sought to define a prognostic [...] Read more.

Triple negative breast cancer (TNBC) represent 15% of breast cancers. Histoclinical features and marketed prognostic gene expression signatures (GES) failed to identify good- and poor-prognosis patients. Tyrosine kinases (TK) represent potential prognostic and/or therapeutic targets for TNBC. We sought to define a prognostic TK GES in a large series of TNBC. mRNA expression and histoclinical data of 6379 early BCs were collected from 16 datasets. We searched for a TK-based GES associated with disease-free survival (DFS) and tested its robustness in an independent validation set. A total of 1226 samples were TNBC. In the learning set of samples (N = 825), we identified a 13-TK GES associated with DFS. This GES was associated with cell proliferation and immune response. In multivariate analysis, it outperformed the previously published GESs and classical prognostic factors in the validation set (N = 401), in which the patients classified as “low-risk” had a 73% 5-year DFS versus 53% for “high-risk” patients (p = 1.85 × 10⁻³). The generation of 100,000 random 13-gene signatures by a resampling scheme showed the non-random nature of our classifier, which was also prognostic for overall survival in multivariate analysis. We identified a robust and non-random 13-TK GES that separated TNBC into subgroups of different prognosis. Clinical and functional validations are warranted. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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15 pages, 1287 KiB

Open AccessArticle

EV-Associated miRNAs from Peritoneal Lavage are a Source of Biomarkers in Endometrial Cancer

by Berta Roman-Canal, Cristian Pablo Moiola, Sònia Gatius, Sarah Bonnin, Maria Ruiz-Miró, Esperanza González, Xavier González-Tallada, Ivanna Llordella, Isabel Hernández, José M. Porcel, Antonio Gil-Moreno, Juan M. Falcón-Pérez, Julia Ponomarenko, Xavier Matias-Guiu and Eva Colas

Cancers 2019, 11(6), 839; https://doi.org/10.3390/cancers11060839 - 18 Jun 2019

Cited by 31 | Viewed by 5457

Abstract

Endometrial cancer (EC) is the sixth most common cancer in women worldwide and is responsible for more than 89,000 deaths every year. Mortality is associated with presence of poor prognostic factors at diagnosis, i.e., diagnosis at an advanced stage, with a high grade [...] Read more.

Endometrial cancer (EC) is the sixth most common cancer in women worldwide and is responsible for more than 89,000 deaths every year. Mortality is associated with presence of poor prognostic factors at diagnosis, i.e., diagnosis at an advanced stage, with a high grade and/or an aggressive histology. Development of novel approaches that would permit us to improve the clinical management of EC patients is an unmet need. In this study, we investigate a novel approach to identify highly sensitive and specific biomarkers of EC using extracellular vesicles (EVs) isolated from the peritoneal lavage of EC patients. EVs of peritoneal lavages of 25 EC patients were isolated and their miRNA content was compared with miRNAs of EVs isolated from the ascitic fluid of 25 control patients. Expression of the EV-associated miRNAs was measured using the Taqman OpenArray technology that allowed us to detect 371 miRNAs. The analysis showed that 114 miRNAs were significantly dysregulated in EC patients, among which eight miRNAs, miRNA-383-5p, miRNA-10b-5p, miRNA-34c-3p, miRNA-449b-5p, miRNA-34c-5p, miRNA-200b-3p, miRNA-2110, and miRNA-34b-3p, demonstrated a classification performance at area under the receiver operating characteristic curve (AUC) values above 0.9. This finding opens an avenue for the use of EV-associated miRNAs of peritoneal lavages as an untapped source of biomarkers for EC. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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22 pages, 24755 KiB

Open AccessArticle

Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy

by Nadiia Lypova, Lilibeth Lanceta, Alana Gipson, Stephanie Vega, Rodolfo Garza-Morales, Kelly M. McMasters, Jason Chesney, Jorge G. Gomez-Gutierrez and Yoannis Imbert-Fernandez

Cancers 2019, 11(5), 684; https://doi.org/10.3390/cancers11050684 - 16 May 2019

Cited by 15 | Viewed by 8414

Abstract

While clinical responses to palbociclib have been promising, metastatic breast cancer remains incurable due to the development of resistance. We generated estrogen receptor-positive (ER+) and ER-negative (ER−) cell line models and determined their permissiveness and cellular responses to an oncolytic adenovirus (OAd) known [...] Read more.

While clinical responses to palbociclib have been promising, metastatic breast cancer remains incurable due to the development of resistance. We generated estrogen receptor-positive (ER+) and ER-negative (ER−) cell line models and determined their permissiveness and cellular responses to an oncolytic adenovirus (OAd) known as Ad5/3-delta24. Analysis of ER+ and ER− palbociclib-resistant cells revealed two clearly distinguishable responses to the OAd. While ER+ palbociclib-resistant cells displayed a hypersensitive phenotype to the effects of the OAd, ER− palbociclib-resistant cells showed a resistant phenotype to the OAd. Hypersensitivity to the OAd in ER+ palbociclib-resistant cells correlated with a decrease in type I interferon (IFN) signaling, an increase in viral entry receptor expression, and an increase in cyclin E expression. OAd resistance in ER− palbociclib-resistant cells correlated with an increase in type I IFN signaling and a marked decrease in viral entry receptor. Using the OAd as monotherapy caused significant cytotoxicity to both ER+ and ER− palbociclib-sensitive cell lines. However, the addition of palbociclib increased the oncolytic activity of the OAd only in ER+ palbociclib-sensitive cells. Our studies provide a mechanistic base for a novel anti-cancer regimen composed of an OAd in combination with palbociclib for the treatment of ER+ breast cancer. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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16 pages, 5726 KiB

Open AccessArticle

TRPC3 Regulates the Proliferation and Apoptosis Resistance of Triple Negative Breast Cancer Cells through the TRPC3/RASA4/MAPK Pathway

by Yan Wang, Yan-Xiang Qi, Zenghua Qi and Suk-Ying Tsang

Cancers 2019, 11(4), 558; https://doi.org/10.3390/cancers11040558 - 18 Apr 2019

Cited by 42 | Viewed by 6439

Abstract

Currently, there is no effective molecular-based therapy for triple-negative breast cancer (TNBC). Canonical transient receptor potential isoform 3 (TRPC3) was previously shown to be upregulated in breast cancer biopsy tissues when compared to normal breast tissues. However, the biological role of TRPC3 in [...] Read more.

Currently, there is no effective molecular-based therapy for triple-negative breast cancer (TNBC). Canonical transient receptor potential isoform 3 (TRPC3) was previously shown to be upregulated in breast cancer biopsy tissues when compared to normal breast tissues. However, the biological role of TRPC3 in breast cancer still remains to be elucidated. In this study, subcellular fractionation followed by Western blot and immunocytochemistry showed that TRPC3 was over-expressed on the plasma membrane of TNBC line MDA-MB-231 when compared to an estrogen receptor-positive cell line MCF-7. TRPC3 blocker Pyr3 and dominant negative of TRPC3 attenuated proliferation, induced apoptosis and sensitized cell death to chemotherapeutic agents in MDA-MB-231 as measured by proliferation assays. Interestingly, Ras GTPase-activating protein 4 (RASA4), a Ca²⁺-promoted Ras-MAPK pathway suppressor, was found to be located on the plasma membrane of MDA-MB-231. Blocking TRPC3 decreased the amount of RASA4 located on the plasma membrane, with concomitant activation of MAPK pathways. Our results suggest that, in TNBC MDA-MB-231 cells, Ca²⁺ influx through TRPC3 channel sustains the presence of RASA4 on the plasma membrane where it inhibits the Ras-MAPK pathway, leading to proliferation and apoptosis resistance. Our study reveals the novel TRPC3-RASA4-MAPK signaling cascade in TNBC cells and suggests that TRPC3 may be exploited as a potential therapeutic target for TNBC. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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20 pages, 4168 KiB

Open AccessArticle

Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance

by Eylem Kulkoyluoglu-Cotul, Brandi Patrice Smith, Kinga Wrobel, Yiru Chen Zhao, Karen Lee Ann Chen, Kadriye Hieronymi, Ozan Berk Imir, Kevin Duong, Caitlin O’Callaghan, Aditi Mehta, Sunati Sahoo, Barbara Haley, Hua Chang, Yosef Landesman and Zeynep Madak-Erdogan

Cancers 2019, 11(4), 479; https://doi.org/10.3390/cancers11040479 - 4 Apr 2019

Cited by 15 | Viewed by 7935

Abstract

A majority of breast cancer specific deaths in women with ERα (+) tumors occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective [...] Read more.

A majority of breast cancer specific deaths in women with ERα (+) tumors occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and the nuclear transport protein XPO1 in overcoming endocrine resistance. Selinexor (SEL), an XPO1 antagonist, has been evaluated in multiple late stage clinical trials in patients with relapsed and/or refractory hematological and solid tumor malignancies. Our transcriptomics analysis showed that 4-Hydroxytamoxifen (4-OHT), SEL alone or their combination induced differential Akt signaling- and metabolism-associated gene expression profiles. Western blot analysis in endocrine resistant cell lines and xenograft models validated differential Akt phosphorylation. Using the Seahorse metabolic profiler, we showed that ERα-XPO1 targeting changed the metabolic phenotype of TAM-resistant breast cancer cells from an energetic to a quiescent profile. This finding demonstrated that combined targeting of XPO1 and ERα rewired the metabolic pathways and shut down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies to improve therapy response in relapsed ERα (+) tumors, our findings show great promise for uncovering the role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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16 pages, 20403 KiB

Open AccessArticle

High Frequency of ERBB2 Activating Mutations in Invasive Lobular Breast Carcinoma with Pleomorphic Features

by Juan Manuel Rosa-Rosa, Tamara Caniego-Casas, Susanna Leskela, Eva Cristobal, Silvia González-Martínez, Esther Moreno-Moreno, Elena López-Miranda, Esther Holgado, Belén Pérez-Mies, Pilar Garrido and José Palacios

Cancers 2019, 11(1), 74; https://doi.org/10.3390/cancers11010074 - 11 Jan 2019

Cited by 34 | Viewed by 5873

Abstract

Background: Characterisation of molecular alterations of pleomorphic lobular carcinoma (PLC), an aggressive subtype of invasive lobular carcinoma (ILC), have not been yet completely accomplished. Methods: To investigate the molecular alterations of invasive lobular carcinoma with pleomorphic features, a total of 39 tumour samples [...] Read more.

Background: Characterisation of molecular alterations of pleomorphic lobular carcinoma (PLC), an aggressive subtype of invasive lobular carcinoma (ILC), have not been yet completely accomplished. Methods: To investigate the molecular alterations of invasive lobular carcinoma with pleomorphic features, a total of 39 tumour samples (in situ and invasive lesions and lymph node metastases) from 27 patients with nuclear grade 3 invasive lobular carcinomas were subjected to morphological, immunohistochemical and massive parallel sequencing analyses. Results: Our observations indicated that invasive lobular carcinomas with pleomorphic features were morphologically and molecularly heterogeneous. All cases showed absence or aberrant expression of E-cadherin and abnormal expression of β-catenin and p120. CDH1 (89%), PIK3CA (33%) and ERRB2 (26%) were the most common mutated genes. ERBB2 mutations preferentially affected the tyrosine-kinase activity domain, being the most frequent the targetable mutation p.L755S (57%). We also observed higher frequency of mutations in ARID1B, KMT2C, MAP3K1, TP53 and ARID1A in PLC than previously reported in classic ILC. Alterations related to progression from in situ to invasive carcinoma and/or to lymph node metastases included TP53 mutation, amplification of PIK3CA and CCND1 and loss of ARID1A expression. Conclusions: The high frequency of ERBB2 mutations observed suggests that ERBB2 mutation testing should be considered in all invasive lobular carcinomas with nuclear grade 3. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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Review

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16 pages, 5128 KiB

Open AccessReview

Imaging of Preclinical Endometrial Cancer Models for Monitoring Tumor Progression and Response to Targeted Therapy

by Heidi Espedal, Tina Fonnes, Kristine E. Fasmer, Camilla Krakstad and Ingfrid S. Haldorsen

Cancers 2019, 11(12), 1885; https://doi.org/10.3390/cancers11121885 - 27 Nov 2019

Cited by 7 | Viewed by 4104

Abstract

Endometrial cancer is the most common gynecologic malignancy in industrialized countries. Most patients are cured by surgery; however, about 15% of the patients develop recurrence with limited treatment options. Patient-derived tumor xenograft (PDX) mouse models represent useful tools for preclinical evaluation of new [...] Read more.

Endometrial cancer is the most common gynecologic malignancy in industrialized countries. Most patients are cured by surgery; however, about 15% of the patients develop recurrence with limited treatment options. Patient-derived tumor xenograft (PDX) mouse models represent useful tools for preclinical evaluation of new therapies and biomarker identification. Preclinical imaging by magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT), single-photon emission computed tomography (SPECT) and optical imaging during disease progression enables visualization and quantification of functional tumor characteristics, which may serve as imaging biomarkers guiding targeted therapies. A critical question, however, is whether the in vivo model systems mimic the disease setting in patients to such an extent that the imaging biomarkers may be translatable to the clinic. The primary objective of this review is to give an overview of current and novel preclinical imaging methods relevant for endometrial cancer animal models. Furthermore, we highlight how these advanced imaging methods depict pathogenic mechanisms important for tumor progression that represent potential targets for treatment in endometrial cancer. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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25 pages, 1238 KiB

Open AccessReview

Proteomic Biomarkers for the Detection of Endometrial Cancer

by Kelechi Njoku, Davide Chiasserini, Anthony D. Whetton and Emma J. Crosbie

Cancers 2019, 11(10), 1572; https://doi.org/10.3390/cancers11101572 - 16 Oct 2019

Cited by 64 | Viewed by 8720

Abstract

Endometrial cancer is the leading gynaecological malignancy in the western world and its incidence is rising in tandem with the global epidemic of obesity. Early diagnosis is key to improving survival, which at 5 years is less than 20% in advanced disease and [...] Read more.

Endometrial cancer is the leading gynaecological malignancy in the western world and its incidence is rising in tandem with the global epidemic of obesity. Early diagnosis is key to improving survival, which at 5 years is less than 20% in advanced disease and over 90% in early-stage disease. As yet, there are no validated biological markers for its early detection. Advances in high-throughput technologies and machine learning techniques now offer unique and promising perspectives for biomarker discovery, especially through the integration of genomic, transcriptomic, proteomic, metabolomic and imaging data. Because the proteome closely mirrors the dynamic state of cells, tissues and organisms, proteomics has great potential to deliver clinically relevant biomarkers for cancer diagnosis. In this review, we present the current progress in endometrial cancer diagnostic biomarker discovery using proteomics. We describe the various mass spectrometry-based approaches and highlight the challenges inherent in biomarker discovery studies. We suggest novel strategies for endometrial cancer detection exploiting biologically important protein biomarkers and set the scene for future directions in endometrial cancer biomarker research. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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13 pages, 959 KiB

Open AccessReview

Adipocytes and microRNAs Crosstalk: A Key Tile in the Mosaic of Breast Cancer Microenvironment

by Erika Bandini, Tania Rossi, Giulia Gallerani and Francesco Fabbri

Cancers 2019, 11(10), 1451; https://doi.org/10.3390/cancers11101451 - 27 Sep 2019

Cited by 20 | Viewed by 4770

Abstract

Breast cancer (BC) is a disease characterized by a high grade of heterogeneity. Consequently, despite the great achievements obtained in the last decades, most of the current therapeutic regimens still fail. The identification of new molecular mechanisms that will increase the knowledge of [...] Read more.

Breast cancer (BC) is a disease characterized by a high grade of heterogeneity. Consequently, despite the great achievements obtained in the last decades, most of the current therapeutic regimens still fail. The identification of new molecular mechanisms that will increase the knowledge of all steps of tumor initiation and growth is mandatory in finding new clinical strategies. The BC microenvironment, consisting of endothelial cells, fibroblasts, immune cells and adipocytes, plays an essential role in regulating BC development, and recently it has gained great attention in the scientific community. In particular, adipose tissue is emerging as an important target to investigate among mammary gland components. The mechanisms underlying BC progression driven by adipocytes are predominantly unexplored, especially that involving the switch from normal adipocytes to the so-called cancer-associated adipocytes (CAAs). MicroRNAs (miRNAs), a class of gene expression modulators, have emerged as the regulators of key oncogenes and tumor suppressor genes that affect multiple pathways of the tumor microenvironment and adipose tissue. This review concerns a presentation of the role of adipocytes in breast tissue, and describes the most recent discoveries about the interplay between adipocytes and miRNAs, which collaborate in the arrangement of a pro-inflammatory and cancerous microenvironment, laying the foundations for new concepts in the prevention and treatment of BC. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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18 pages, 283 KiB

Open AccessReview

The Use of microRNAs in the Management of Endometrial Cancer: A Meta-Analysis

by Romain Delangle, Tiphaine De Foucher, Annette K. Larsen, Michèle Sabbah, Henri Azaïs, Sofiane Bendifallah, Emile Daraï, Marcos Ballester, Céline Mehats, Catherine Uzan and Geoffroy Canlorbe

Cancers 2019, 11(6), 832; https://doi.org/10.3390/cancers11060832 - 16 Jun 2019

Cited by 44 | Viewed by 4391

Abstract

Introduction: Endometrial cancer (EC) is the most important gynecological cancer in terms of incidence. microRNAs (miRs), which are post-transcriptional regulators implicated in a variety of cellular functions including carcinogenesis, are particularly attractive candidates as biomarkers. Indeed, several studies have shown that the [...] Read more.

Introduction: Endometrial cancer (EC) is the most important gynecological cancer in terms of incidence. microRNAs (miRs), which are post-transcriptional regulators implicated in a variety of cellular functions including carcinogenesis, are particularly attractive candidates as biomarkers. Indeed, several studies have shown that the miR expression pattern appears to be associated with prognostic factors in EC. Our objective is to review the current knowledge of the role of miRs in carcinogenesis and tumor progression and their association with the prognosis of endometrial cancer. Materials and Method: We performed a literature search for miR expression in EC using MEDLINE, PubMed (the Internet portal of the National Library of Medicine) and The Cochrane Library, Cochrane databases “Cochrane Reviews” and “Clinical Trials” using the following keywords: microRNA, endometrial cancer, prognosis, diagnosis, lymph node, survival, plasma, FFPE (formalin-fixed, paraffin-embedded). The miRs were classified and presented according to their expression levels in cancer tissue in relation to different prognostic factors. Results: Data were collected from 74 original articles and 8 literature reviews which described the expression levels of 261 miRs in ECs, including 133 onco-miRs, 110 miR onco-suppressors, and 18 miRs with discordant functions. The review identified 30 articles studying the expression pattern of miR in neoplastic endometrial tissue compared to benign and/or hyperplastic tissues, 12 articles detailing the expression profile of miRs as a function of lymph node status, and 14 articles that detailed the expression pattern of miRs in endometrial tumor tissue according to overall survival or in the absence of recurrence. Conclusions: The findings presented here suggest that miR analysis merits a role as a prognostic factor in the management of patients with endometrial cancer. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

15 pages, 1050 KiB

Open AccessReview

Exploring lncRNA-Mediated Regulatory Networks in Endometrial Cancer Cells and the Tumor Microenvironment: Advances and Challenges

by Peixin Dong, Ying Xiong, Junming Yue, Sharon J. B. Hanley, Noriko Kobayashi, Yukiharu Todo and Hidemichi Watari

Cancers 2019, 11(2), 234; https://doi.org/10.3390/cancers11020234 - 16 Feb 2019

Cited by 77 | Viewed by 7108

Abstract

Recent studies have revealed both the promise and challenges of targeting long non-coding RNAs (lncRNAs) to diagnose and treat endometrial cancer (EC). LncRNAs are upregulated or downregulated in ECs compared to normal tissues and their dysregulation has been linked to tumor grade, FIGO [...] Read more.

Recent studies have revealed both the promise and challenges of targeting long non-coding RNAs (lncRNAs) to diagnose and treat endometrial cancer (EC). LncRNAs are upregulated or downregulated in ECs compared to normal tissues and their dysregulation has been linked to tumor grade, FIGO stage, the depth of myometrial invasion, lymph node metastasis and patient survival. Tumor suppressive lncRNAs (GAS5, MEG3, FER1L4 and LINC00672) and oncogenic lncRNAs (CCAT2, BANCR, NEAT1, MALAT1, H19 and Linc-RoR) have been identified as upstream modulators or downstream effectors of major signaling pathways influencing EC metastasis, including the PTEN/PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, WNT/β-catenin and p53 signaling pathways. TUG1 and TDRG1 stimulate the VEGF-A pathway. PCGEM1 is implicated in activating the JAK/STAT3 pathway. Here, we present an overview of the expression pattern, prognostic value, biological function of lncRNAs in EC cells and their roles within the tumor microenvironment, focusing on the influence of lncRNAs on established EC-relevant pathways. We also describe the emerging classification of EC subtypes based on their lncRNA signature and discuss the clinical implications of lncRNAs as valuable biomarkers for EC diagnosis and potential targets for EC treatment. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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