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P53, EMT and DNA Repair: Novel Links Impacting Cancer Progression...
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P53, EMT and DNA Repair: Novel Links Impacting Cancer Progression and Drug Response

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 August 2024) | Viewed by 4222

Special Issue Editor

Dr. Cai M. Roberts

E-Mail Website
Guest Editor
Department of Pharmacology, Midwestern University, Downers Grove, IL, USA
Interests: epithelial to mesenchymal transition; TWIST1; BRCA mutation; p53 mutation; ovarian cancer; chemoresistance; cancer pharmacology

Special Issue Information

Dear Colleagues,

Major challenges in the treatment of carcinomas are metastatic spread and the development of therapeutic resistance. Much work has characterized the changes that tumor cells undergo in the process of metastasis, particularly epithelial to mesenchymal transition (EMT). This developmental program is often reactivated in cancers, leading to loss of cell polarity and adhesion and the adoption of an aggressive, motile phenotype. In recent years, EMT has been linked to resistance to several chemotherapeutic agents and to populations alternately dubbed tumor-initiating cells or cancer stem cells. The first aim of this Special Issue is to bring together the latest work on the role of EMT in cancer recurrence and resistance.

P53, a regulator of genomic integrity, is commonly mutated in cancers, with variants appearing in virtually all serous ovarian cancers, half of all non-small cell lung cancers, and a third of breast cancers, among others. In breast, ovarian, and prostate cancers, mutations in the BRCA genes can give rise to tumors but also leave these tumors vulnerable to inhibitors of Poly(ADP-ribose) polymerase. Determining how dysregulation of DNA repair via mutations in these and other genes impacts drug responses, and how the metastatic process and EMT factor in, will be essential for the design of new treatment strategies and comprises the second aim of this Special Issue.

I am pleased to invite original research articles, reviews, and commentaries, and I look forward to receiving your contributions.

Dr. Cai M. Roberts
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 submissions that pass pre-check are 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 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 semimonthly 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 2900 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.

Keywords

  • epithelial to mesenchymal transition
  • metastasis
  • DNA repair
  • p53
  • chemoresistance
  • cancer stem cells
  • drug discovery

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Published Papers (2 papers)

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Research

21 pages, 4290 KiB  
Article
DNA Damage Response in Early Breast Cancer: A Phase III Cohort in the Phobos Study
by Eriseld Krasniqi, Cristiana Ercolani, Anna Di Benedetto, Francesca Sofia Di Lisa, Lorena Filomeno, Teresa Arcuri, Claudio Botti, Fabio Pelle, Flavia Cavicchi, Sonia Cappelli, Maddalena Barba, Laura Pizzuti, Marcello Maugeri-Saccà, Luca Moscetti, Antonino Grassadonia, Nicola Tinari, Giuseppe Sanguineti, Silvia Takanen, Davide Fragnito, Irene Terrenato, Simonetta Buglioni, Letizia Perracchio, Agnese Latorre, Ruggero De Maria, Matteo Pallocca, Gennaro Ciliberto, Francesco Giotta and Patrizia Viciadd Show full author list remove Hide full author list
Cancers 2024, 16(15), 2628; https://doi.org/10.3390/cancers16152628 - 23 Jul 2024
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Abstract
We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed [...] Read more.
We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed no disease-free survival (DFS) or overall survival (OS) differences with the addition of docetaxel (D) to epirubicine-cyclophosphamide (EC). Immunohistochemistry was employed to assess the expression of DDR phosphoproteins (pATM, pATR, pCHK1, γH2AX, pRPA32, and pWEE1) in tumor tissue, and their association with clinical outcomes was evaluated through the Cox elastic net model. Over an extended follow-up of 234 months, we confirmed no significant differences in DFS or OS between patients treated with EC and those receiving D → EC. A DDR risk score, inversely driven by ATM and ATR expression, emerged as an independent prognostic factor for both DFS (HR = 0.41, p < 0.0001) and OS (HR = 0.61, p = 0.046). Further validation in a public adjuvant BC cohort was possible only for ATM, confirming its protective role. Overall, our findings confirm the potential role of the DDR pathway in BC prognostication and in shaping treatment strategies advocating for an integrated approach, combining molecular markers with clinical–pathological factors. Full article
(This article belongs to the Special Issue P53, EMT and DNA Repair: Novel Links Impacting Cancer Progression and Drug Response)
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17 pages, 3607 KiB  
Article
Transforming Growth Factor Beta and Epithelial to Mesenchymal Transition Alter Homologous Recombination Repair Gene Expression and Sensitize BRCA Wild-Type Ovarian Cancer Cells to Olaparib
by Cai M. Roberts, Mehida Rojas-Alexandre, Ruth E. Hanna, Z. Ping Lin and Elena S. Ratner
Cancers 2023, 15(15), 3919; https://doi.org/10.3390/cancers15153919 - 1 Aug 2023
Cited by 4 | Viewed by 2138
Abstract
Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, largely due to metastasis and drug resistant recurrences. Fifteen percent of ovarian tumors carry mutations in BRCA1 or BRCA2, rendering them vulnerable to treatment with PARP inhibitors such as olaparib. Recent studies have [...] Read more.
Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, largely due to metastasis and drug resistant recurrences. Fifteen percent of ovarian tumors carry mutations in BRCA1 or BRCA2, rendering them vulnerable to treatment with PARP inhibitors such as olaparib. Recent studies have shown that TGFβ can induce “BRCAness” in BRCA wild-type cancer cells. Given that TGFβ is a known driver of epithelial to mesenchymal transition (EMT), and the connection between EMT and metastatic spread in EOC and other cancers, we asked if TGFβ and EMT alter the susceptibility of EOC to PARP inhibition. Epithelial EOC cells were transiently treated with soluble TGFβ, and their clonogenic potential, expression, and function of EMT and DNA repair genes, and response to PARP inhibitors compared with untreated controls. A second epithelial cell line was compared to its mesenchymal derivative for EMT and DNA repair gene expression and drug responses. We found that TGFβ and EMT resulted in the downregulation of genes responsible for homologous recombination (HR) and sensitized cells to olaparib. HR efficiency was reduced in a dose-dependent manner. Furthermore, mesenchymal cells displayed sensitivity to olaparib, cisplatin, and the DNA-PK inhibitor Nu-7441. Therefore, the treatment of disseminated, mesenchymal tumors may represent an opportunity to expand the clinical utility of PARP inhibitors and similar agents. Full article
(This article belongs to the Special Issue P53, EMT and DNA Repair: Novel Links Impacting Cancer Progression and Drug Response)
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