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Molecular Therapeutics of Breast Cancer
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Molecular Therapeutics of Breast Cancer

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 December 2022) | Viewed by 32331

Special Issue Editor

Dr. Amir Sonnenblick

E-Mail Website
Guest Editor
1. Dept Oncol, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Interests: breast cancer; molecular therapeutics; targeted therapy

Special Issue Information

Dear Colleagues, 

Breast cancer (BC) has been diagnosed since ancient times. Hippocrates, "the father of Western medicine", first suggested that BC was a systemic disease. The fundamentals of his theory stood for more than 2000 years until 1757 when Henri Le Dran, a French physician, suggested that surgical removal of the tumor could cure BC as it was a local disease with local origin. Extensive clinical and basic research have conceptually changed the way we perceive breast cancer, shifting from an emphasis on local therapy to an emphasis on systemic treatment options. In recent years, different molecular alterations governing BC progression have led to potential novel targeted therapies. The present Special Issue will focus on the evolution of BC treatment philosophy in the last years and the shift from an emphasis on local therapy to an emphasis on systemic treatment options and molecular therapeutics.

Dr. Amir Sonnenblick
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 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

  • breast cancer
  • molecular therapeutics
  • systemic treatment
  • targeted therapies
  • PIK3CA
  • mTORC
  • PDL1/PD1
  • ER
  • HER2
  • prognostic markers
  • predictive markers

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Published Papers (7 papers)

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Research

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7 pages, 1473 KiB  
Article
Alpelisib Efficacy in Hormone Receptor-Positive HER2-Negative PIK3CA-Mutant Advanced Breast Cancer Post-Everolimus Treatment
by Ari Raphael, Mali Salmon-Divon, Jessica Epstein, Tamar Zahavi, Amir Sonnenblick and Shlomit S. Shachar
Genes 2022, 13(10), 1763; https://doi.org/10.3390/genes13101763 - 29 Sep 2022
Cited by 1 | Viewed by 3179
Abstract
This real-world cohort analysis assessed the efficacy of alpelisib and endocrine treatment (ET) combinations in a post-everolimus setting. Thirteen women who started alpelisib and ET at standard doses between 2018 and 2022 for advanced breast cancer (ABC), after undergoing CDK4/6i and everolimus treatment, [...] Read more.
This real-world cohort analysis assessed the efficacy of alpelisib and endocrine treatment (ET) combinations in a post-everolimus setting. Thirteen women who started alpelisib and ET at standard doses between 2018 and 2022 for advanced breast cancer (ABC), after undergoing CDK4/6i and everolimus treatment, were eligible for the study entry. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR) and clinical benefit rate (CBR), with different molecular profiling. The patients had previously received a median of four (range 3–8) systemic treatments, including CDK4/6i and everolimus. The median PFS on alpelisib was 5.5 months (range 0.5–10), and four women each had an ORR and three (23%) had a stable disease. The 6-month CBR was 46.1%, similar to the BYLeive study cohort C (47.8%). Notably, our cohort included patients with a long CBR under everolimus treatment (median 6 months, range 1–18); however, the responses to alpelisib and everolimus were not correlated (Pearson r = −0.23, p = 0.44). The PIK3CA, P53, ARID, GATA3, and ESR1 mutations were not associated with the 6-month CBR. Despite heavy pre-treatments, including everolimus, alpelisib was clinically relevant in our cohort, even among patients with an ESR1 mutation. The best treatment sequence for PIK3CA/mTOR inhibitors warrants examination in future trials on PIK3CA-mutant inpatients with luminal ABC. Full article
(This article belongs to the Special Issue Molecular Therapeutics of Breast Cancer)
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7 pages, 1365 KiB  
Article
Potential Refinement of Recurrence Score by pSTAT3 Status
by Albert Grinshpun, Yogev Cohen, Aviad Zick, Luna Kadouri, Tamar Hamburger, Benjamin Nisman, Tanir M. Allweis, Gabriela Oprea, Tamar Peretz, Beatrice Uziely and Amir Sonnenblick
Genes 2022, 13(3), 438; https://doi.org/10.3390/genes13030438 - 27 Feb 2022
Cited by 1 | Viewed by 2375
Abstract
The likelihood of recurrence in breast cancer patients with hormone receptor-positive (HR-positive) tumors is influenced by clinical, histopathological, and molecular features. Recent studies suggested that activated STAT3 (pSTAT3) might serve as a biomarker of outcome in breast cancer patients. In the present work, [...] Read more.
The likelihood of recurrence in breast cancer patients with hormone receptor-positive (HR-positive) tumors is influenced by clinical, histopathological, and molecular features. Recent studies suggested that activated STAT3 (pSTAT3) might serve as a biomarker of outcome in breast cancer patients. In the present work, we have analyzed the added value of pSTAT3 to OncotypeDx Recurrence Score (RS) in patient prognostication. We have found that patients with low RS (<26) and low pSTAT3 might represent a population at a higher risk for cancer recurrence. Furthermore, we have observed that a positive pSTAT3 score alone can be a favorable marker for patients with HR-positive breast cancer under the age of 50. In an era of personalized medicine, these findings warrant further appraisal of chemotherapy benefit in this population. Full article
(This article belongs to the Special Issue Molecular Therapeutics of Breast Cancer)
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15 pages, 1850 KiB  
Article
UC.183, UC.110, and UC.84 Ultra-Conserved RNAs Are Mutually Exclusive with miR-221 and Are Engaged in the Cell Cycle Circuitry in Breast Cancer Cell Lines
by Fabio Corrà, Francesca Crudele, Federica Baldassari, Nicoletta Bianchi, Marco Galasso, Linda Minotti, Chiara Agnoletto, Gianpiero Di Leva, Federica Brugnoli, Eva Reali, Valeria Bertagnolo, Andrea Vecchione and Stefano Volinia
Genes 2021, 12(12), 1978; https://doi.org/10.3390/genes12121978 - 13 Dec 2021
Cited by 5 | Viewed by 2689
Abstract
In the human genome, there are about 600 ultra-conserved regions (UCRs), long DNA sequences extremely conserved in vertebrates. We performed a large-scale study to quantify transcribed UCR (T-UCR) and miRNA levels in over 6000 cancer and normal tissue samples to find possible correlation [...] Read more.
In the human genome, there are about 600 ultra-conserved regions (UCRs), long DNA sequences extremely conserved in vertebrates. We performed a large-scale study to quantify transcribed UCR (T-UCR) and miRNA levels in over 6000 cancer and normal tissue samples to find possible correlation between these kinds of regulatory molecules. Our analysis evidenced several non-coding RNAs showing negative co-regulation with miRNAs; among them, we focused on miR-221 to investigate any relationship with its pivotal role in the cell cycle. We have chosen breast cancer as model, using two cell lines with different phenotypes to carry out in vitro treatments with siRNAs against T-UCRs. Our results demonstrate that the expression of uc.183, uc.110, and uc.84 T-UCRs is mutually exclusive with miR-221 and is engaged in the regulation of CDKN1B expression. In addition, tests with a set of anticancer drugs, including BYL719, AZD5363, AZD8055, AZD7762, and XL765, revealed the modulation of specific T-UCRs without alteration of miR-221 levels. Full article
(This article belongs to the Special Issue Molecular Therapeutics of Breast Cancer)
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7 pages, 1044 KiB  
Communication
RANK-C Expression Sensitizes ER-Negative, EGFR-Positive Breast Cancer Cells to EGFR-Tyrosine Kinase Inhibitors (TKIs)
by Chaido Sirinian, Anastasios D. Papanastasiou, Soren E. Degn, Theodora Frantzi, Christos Aronis, Dimitrios Chaniotis, Thomas Makatsoris, Angelos Koutras and Haralabos P. Kalofonos
Genes 2021, 12(11), 1686; https://doi.org/10.3390/genes12111686 - 23 Oct 2021
Viewed by 2652
Abstract
Background: We have previously shown that overexpression of RANK-c in ER-negative breast cancer cell lines attenuates aggressive properties of cancer cells, partially through a RANK-c/EGFR interaction. EGFR inhibition through TKIs in breast cancer has been tested in triple-negative disease settings with limited clinical [...] Read more.
Background: We have previously shown that overexpression of RANK-c in ER-negative breast cancer cell lines attenuates aggressive properties of cancer cells, partially through a RANK-c/EGFR interaction. EGFR inhibition through TKIs in breast cancer has been tested in triple-negative disease settings with limited clinical benefit for patients. Here we test if expression of RANK-c in ER-negative breast cancer cells in conjunction with treatment with TK inhibitors (erlotinib or gefitinib) can affect survival and colony-forming capacity of cancer cells. Methods: Stably expressing MDA-MB-231-RANK-c and SKBR3-RANK-c cells were employed to test proliferation and colony formation in the presence of TKIs. In addition, Western blot analysis was performed to dissect EGFR related signaling cascades upon TK inhibition in the presence of RANK-c. Results: Interestingly the two RANK-c expressing, ER-negative cells lines presented with a distinct phenotype concerning TKI sensitivity upon treatment. MDA-MB-231-RANK-c cells had a higher sensitivity upon gefitinib treatment, while erlotinib decreased the proliferation rate of SKBR3-RANK-c cells. Further, colony formation assays for MDA-MB-231-RANK-c cells showed a decrease in the number and size of colonies developed in the presence of erlotinib. In addition, RANK-c seems to alter signaling through EGFR after TKI treatment in a cell type-specific manner. Conclusions: Our results indicate that ER-negative breast cancer cells that express RANK-c alter their sensitivity profile against tyrosine kinase inhibitors (erlotinib and gefitinib) in a cell type-specific and culture substrate-dependent manner. Full article
(This article belongs to the Special Issue Molecular Therapeutics of Breast Cancer)
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Review

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22 pages, 1237 KiB  
Review
Antibody-Drug Conjugates for the Treatment of HER2-Positive Breast Cancer
by Mariana K. Najjar, Sara G. Manore, Angelina T. Regua and Hui-Wen Lo
Genes 2022, 13(11), 2065; https://doi.org/10.3390/genes13112065 - 8 Nov 2022
Cited by 35 | Viewed by 8401
Abstract
Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20–30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of [...] Read more.
Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20–30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of HER2-directed therapeutics is an important advancement in targeting invasive breast cancer. Despite the efficacy of anti-HER2 monoclonal antibodies, they are still being combined with adjuvant chemotherapy to improve overall patient outcomes. Recently, significant progress has been made towards the development of a class of therapeutics known as antibody-drug conjugates (ADCs), which leverage the high specificity of HER2-targeted monoclonal antibodies with the potent cytotoxic effects of various small molecules, such as tubulin inhibitors and topoisomerase inhibitors. To date, two HER2-targeting ADCs have been approved by the FDA for the treatment of HER2-positive breast cancer: Ado-trastuzumab emtansine (T-DM1; Kadcyla®) and fam-trastuzumab deruxtecan-nxki (T-Dxd; Enhertu®). Kadcyla and Enhertu are approved for use as a second-line treatment after trastuzumab-taxane-based therapy in patients with HER2-positive breast cancer. The success of ADCs in the treatment of HER2-positive breast cancer provides novel therapeutic advancements in the management of the disease. In this review, we discuss the basic biology of HER2, its downstream signaling pathways, currently available anti-HER2 therapeutic modalities and their mechanisms of action, and the latest clinical and safety characteristics of ADCs used for the treatment of HER2-positive breast cancer. Full article
(This article belongs to the Special Issue Molecular Therapeutics of Breast Cancer)
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10 pages, 773 KiB  
Review
Cellular Senescence in Normal Mammary Gland and Breast Cancer. Implications for Cancer Therapy
by Chaido Sirinian, Stavros Peroukidis, Katharina Kriegsmann, Dimitrios Chaniotis, Angelos Koutras, Mark Kriegsmann and Anastasios D. Papanastasiou
Genes 2022, 13(6), 994; https://doi.org/10.3390/genes13060994 - 1 Jun 2022
Cited by 10 | Viewed by 4298
Abstract
Cellular senescence (CS) is a major homeostatic biological process, which plays a key role in normal tissue development and provides protection from stressful cell insults. The role of CS in mammary-gland development and breast cancer is not well understood. While there is a [...] Read more.
Cellular senescence (CS) is a major homeostatic biological process, which plays a key role in normal tissue development and provides protection from stressful cell insults. The role of CS in mammary-gland development and breast cancer is not well understood. While there is a lack of experimental data on the role of CS in the development of the pre-pubertal mammary gland, there is evidence for a biphasic senescence response in adult normal-mammary-epithelial cells, where the bypass of the first senescence barrier (M0) seems to be a key step in the development of premalignant lesions, with genetic abnormalities that resemble in situ breast carcinoma. Further, there is accumulating evidence for the role of cellular senescence in breast-cancer response, regarding treatment and patient outcome. Here, we review the current literature on cellular senescence, in epithelial-mammary cells, breast-cancer cells, and breast-tumor-microenvironment-resident cells. Furthermore, we discuss its putative role in breast-cancer response, regarding treatment and disease progression. In addition, we provide preliminary evidence of CS in breast-cancer-microenvironment cells, such as tumor-associated fibroblasts and tumor-infiltrating lymphocytes, by employing the novel GL13 lipofuscin stain, as a marker of cellular senescence. Full article
(This article belongs to the Special Issue Molecular Therapeutics of Breast Cancer)
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12 pages, 986 KiB  
Review
The History of Early Breast Cancer Treatment
by Judith Ben-Dror, Michal Shalamov and Amir Sonnenblick
Genes 2022, 13(6), 960; https://doi.org/10.3390/genes13060960 - 27 May 2022
Cited by 31 | Viewed by 7717
Abstract
“The story of cancer is the story of human ingenuity, resilience, and perseverance, but also of hubris, paternalism, and misperception” (Siddhartha Mukherjee). The present review discusses the evolution of early breast cancer (BC) treatment philosophy in the last 50 years and the shift [...] Read more.
“The story of cancer is the story of human ingenuity, resilience, and perseverance, but also of hubris, paternalism, and misperception” (Siddhartha Mukherjee). The present review discusses the evolution of early breast cancer (BC) treatment philosophy in the last 50 years and the shift from an emphasis on local therapy to an emphasis on systemic precision treatment options. Full article
(This article belongs to the Special Issue Molecular Therapeutics of Breast Cancer)
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