Special Issue "New Insights into Breast and Endometrial Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 31 October 2019

Special Issue Editor

Guest Editor
Dr. Yasuhiro Miki

Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science (IRIDeS), Tohoku University, 2-1 Seiryo-machi, Sendai, Miyagi 9808575, Japan
Website | E-Mail
Interests: endocrine-related cancer; intracrine; cancer microenvironment; psychological stress and endocrine disruption

Special Issue Information

Dear Colleagues,

Cancers of the breast and endometrium are amongst the most common cancers affecting women. In many cases, it is also well known that these cancers show estrogen-dependent proliferation; therefore, hormone therapy strategies are employed. Tamoxifen is an effective hormonal therapy that is traditionally used for estrogen receptor-positive breast cancer patients. However, in endometrial cancer, it is well established that tamoxifen treatment increases the risk of poor prognosis type of endometrial cancer.

All breast cancers, except for triple-negative breast cancer (TNBC), are classified by the expression of biomarkers, such as estrogen receptor, progesterone receptor, and HER2. In TNBC patients, treatment with hormone therapy or HER2 inhibitors is ineffective; therefore, the discovery of novel therapeutic targets is crucial. Type I endometrial cancer, commonly known as an endometrioid, is a prototype estrogen-dependent tumor. Conversely, type II endometrial cancers, including serous and clear cell types, are estrogen-independent and are known to have a poor prognosis.

There are similarities and differences in the behavior of breast and endometrial cancer cells. This Special Issue will focus on recent advances in epidemiology and clinical, molecular, and biochemical research in breast and/or endometrial cancers, with the aim of expanding the understanding of these tumors.

Contributions on these related topics are welcome, including original research, case reports, and reviews. We also welcome submissions from young researchers, including postdocs and students.

Dr. Yasuhiro Miki
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (4 papers)

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Research

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Open AccessArticle TRPC3 Regulates the Proliferation and Apoptosis Resistance of Triple Negative Breast Cancer Cells through the TRPC3/RASA4/MAPK Pathway
Cancers 2019, 11(4), 558; https://doi.org/10.3390/cancers11040558
Received: 1 March 2019 / Revised: 13 April 2019 / Accepted: 16 April 2019 / Published: 18 April 2019
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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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Open AccessArticle Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance
Cancers 2019, 11(4), 479; https://doi.org/10.3390/cancers11040479
Received: 27 February 2019 / Revised: 29 March 2019 / Accepted: 29 March 2019 / Published: 4 April 2019
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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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Open AccessArticle High Frequency of ERBB2 Activating Mutations in Invasive Lobular Breast Carcinoma with Pleomorphic Features
Received: 16 November 2018 / Revised: 30 December 2018 / Accepted: 7 January 2019 / Published: 11 January 2019
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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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Open AccessReview Exploring lncRNA-Mediated Regulatory Networks in Endometrial Cancer Cells and the Tumor Microenvironment: Advances and Challenges
Cancers 2019, 11(2), 234; https://doi.org/10.3390/cancers11020234
Received: 17 January 2019 / Revised: 7 February 2019 / Accepted: 10 February 2019 / Published: 16 February 2019
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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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