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1.
Cancer Treat Res Commun ; 27: 100321, 2021.
Article in English | MEDLINE | ID: covidwho-1385378

ABSTRACT

BACKGROUND: ACE2 a key molecule of the Renin-Angiotensin system has been identified as the receptor for SARS-CoV-2 entry into human cells. In the context of human cancers, there is evidence that ACE2 might function as a tumor suppressor. The expression levels of ACE2 among the different subtypes of breast cancer has not been investigated. METHODS: We have examined the differential expression of ACE2 and its correlation with prognosis in breast cancer subtypes using the METABRIC (n = 1898) and TCGA (n = 832) cohorts. Correlations were evaluated by Pearsons's correlation co-efficient and Kaplan-Meier analysis was used to estimate differences in disease-free survival between the ACE2 high and ACE2 low groups. RESULTS: There is minimal expression of ACE2 in the luminal classes, but significantly higher levels in the Basal-like and HER2-enriched subclasses. Metastatic biopsies of these tumor types also show enhanced expression of ACE2. High levels of ACE2 correlated with decreased disease-free survival in the HER2-enriched subtype, and it was positively correlated with EGFR expression. CONCLUSION: These observations suggest ACE2 might function as a context dependent factor driving tumor progression in breast cancer and permit new opportunities for targeted therapy.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Receptor, ErbB-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/therapy , Cohort Studies , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Multivariate Analysis , Prognosis
2.
J Mammary Gland Biol Neoplasia ; 26(3): 221-226, 2021 09.
Article in English | MEDLINE | ID: covidwho-1375665

ABSTRACT

The twelfth annual workshop of the European Network for Breast Development and Cancer focused on methods in mammary gland biology and breast cancer, was scheduled to take place on March 26-28, 2020, in Weggis, Switzerland. Due to the COVID-19 pandemic, the meeting was rescheduled twice and eventually happened as a virtual meeting on April 22 and 23, 2021. The main topics of the meeting were branching and development of the mammary gland, tumor microenvironment, circulating tumor cells, tumor dormancy and breast cancer metastasis. Novel and unpublished findings related to these topics were presented, with a particular focus on the methods used to obtain them. Virtual poster sessions were a success, with many constructive and fruitful interactions between researchers and covered many areas of mammary gland biology and breast cancer.


Subject(s)
Biomedical Research/methods , Breast Neoplasms/pathology , Mammary Glands, Human/pathology , Biomarkers, Tumor/metabolism , Breast Neoplasms/diagnosis , Breast Neoplasms/metabolism , Breast Neoplasms/therapy , Combined Modality Therapy , Europe , Female , Humans , Mammary Glands, Human/growth & development , Mammary Glands, Human/metabolism , Neoplasm Metastasis , Neoplasm Staging , Neoplastic Cells, Circulating , Prognosis , Tumor Microenvironment
3.
Int J Mol Sci ; 22(14)2021 Jul 12.
Article in English | MEDLINE | ID: covidwho-1308363

ABSTRACT

The cytoskeletal protein vimentin is secreted under various physiological conditions. Extracellular vimentin exists primarily in two forms: attached to the outer cell surface and secreted into the extracellular space. While surface vimentin is involved in processes such as viral infections and cancer progression, secreted vimentin modulates inflammation through reduction of neutrophil infiltration, promotes bacterial elimination in activated macrophages, and supports axonal growth in astrocytes through activation of the IGF-1 receptor. This receptor is overexpressed in cancer cells, and its activation pathway has significant roles in general cellular functions. In this study, we investigated the functional role of extracellular vimentin in non-tumorigenic (MCF-10a) and cancer (MCF-7) cells through the evaluation of its effects on cell migration, proliferation, adhesion, and monolayer permeability. Upon treatment with extracellular recombinant vimentin, MCF-7 cells showed increased migration, proliferation, and adhesion, compared to MCF-10a cells. Further, MCF-7 monolayers showed reduced permeability, compared to MCF-10a monolayers. It has been shown that the receptor binding domain of SARS-CoV-2 spike protein can alter blood-brain barrier integrity. Surface vimentin also acts as a co-receptor between the SARS-CoV-2 spike protein and the cell-surface angiotensin-converting enzyme 2 receptor. Therefore, we also investigated the permeability of MCF-10a and MCF-7 monolayers upon treatment with extracellular recombinant vimentin, and its modulation of the SARS-CoV-2 receptor binding domain. These findings show that binding of extracellular recombinant vimentin to the cell surface enhances the permeability of both MCF-10a and MCF-7 monolayers. However, with SARS-CoV-2 receptor binding domain addition, this effect is lost with MCF-7 monolayers, as the extracellular vimentin binds directly to the viral domain. This defines an influence of extracellular vimentin in SARS-CoV-2 infections.


Subject(s)
Breast Neoplasms/pathology , Breast/pathology , Cell Membrane Permeability , Extracellular Matrix/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Vimentin/metabolism , Breast/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cells, Cultured , Female , Humans , Protein Domains , Spike Glycoprotein, Coronavirus/genetics , Vimentin/genetics
4.
J Clin Pharmacol ; 61(8): 1096-1105, 2021 08.
Article in English | MEDLINE | ID: covidwho-1130518

ABSTRACT

PERJETA (pertuzumab), administered with Herceptin (trastuzumab), is used in the treatment of human epidermal growth factor receptor 2-positive breast cancer. Pertuzumab is currently approved with an initial loading dose of 840 mg, followed by a 420-mg maintenance dose intravenously every 3 weeks. A reloading dose is required if there is a ≥6-week delay in treatment. In response to the potential treatment disruption due to COVID-19, the impact of dose delays and alternative dosing regimens on intravenous pertuzumab for human epidermal growth factor receptor 2-positive breast cancer treatment is presented. Simulations were conducted by using the validated population pharmacokinetic model for pertuzumab, and included (1) 4-, 6-, and 9-week dose delays of the 840 mg/420 mg every 3 weeks dosing regimen and (2) 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks alternative dosing regimens. Simulations were compared with the currently approved pertuzumab dosing regimen. The simulations in 1000 virtual patients showed that a dose reload (840 mg) is required following a dose delay of ≥6 weeks to maintain comparable Ctrough (lowest concentration before the next dose is given) levels to clinical trials. The 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks alternative dosing regimens decrease median steady-state Ctrough by ≈40% compared with the approved regimen, and <90% of patients will be above the target Ctrough . Thus, the alternative 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks pertuzumab dosing regimens are not recommended. Flexibility for intravenous PERJETA-based regimens is available with an alternative route of pertuzumab administration (subcutaneous vs intravenous).


Subject(s)
Antibodies, Monoclonal, Humanized , Breast Neoplasms/drug therapy , Dose-Response Relationship, Drug , Maintenance Chemotherapy/methods , Receptor, ErbB-2/antagonists & inhibitors , Time-to-Treatment , Trastuzumab , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , COVID-19/epidemiology , COVID-19/prevention & control , Computer Simulation , Consolidation Chemotherapy/methods , Drug Administration Routes , Drug Administration Schedule , Female , Humans , Infection Control/methods , SARS-CoV-2 , Trastuzumab/administration & dosage , Trastuzumab/pharmacokinetics
6.
Cell Transplant ; 30: 963689721991477, 2021.
Article in English | MEDLINE | ID: covidwho-1058182

ABSTRACT

TRANSLATIONAL RELEVANCE: No prophylactic treatments for COVID-19 have been clearly proven and found. In this pandemic context, cancer patients constitute a particularly fragile population that would benefit the best from such treatments, a present unmet need. TMPRSS2 is essential for COVID-19 replication cycle and it is under androgen control. Estrogen and androgen receptor dependent cues converge on TMPRSS2 regulation through different mechanisms of action that can be blocked by the use of hormonal therapies. We believe that there is enough body of evidence to foresee a prophylactic use of hormonal therapies against COVID-19 and this hypothesis can be easily tested on cohorts of breast and prostate cancer patients who follow those regimens. In case of pandemic, if the protective effect of hormonal therapies will be proven on cancer patients, the use of specific hormonal therapies could be extended to other oncological groups and to healthy individuals to decrease the overall risk of infection by SARS-CoV-2.Given the COVID-19 coronavirus emergency, a special focus is needed on the impact of this rapidly spreading viral infection on cancer patients. Androgen receptor (AR) signaling in the transmembrane protease serine 2 (TMPRSS2) regulation is emerging as an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility. In our study, we analyzed AR and TMPRSS2 expression in 17,352 normal and 9,556 cancer tissues from public repositories and stratified data according to sex and age. The emerging picture is that some patient groups may be particularly susceptible to SARS-CoV-2 infection and may benefit from antiandrogen- or tamoxifen-based therapies. These findings are relevant to choose proper treatments in order to protect cancer patients from concomitant SARS-CoV-2 contagion and related symptoms and put forward the idea that hormonal therapies could be used as prophylactic agents against COVID-19.


Subject(s)
Androgen Receptor Antagonists/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/complications , COVID-19/complications , Estrogen Antagonists/therapeutic use , Prostatic Neoplasms/complications , Tamoxifen/therapeutic use , Androgen Receptor Antagonists/pharmacology , Antineoplastic Agents, Hormonal/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , COVID-19/drug therapy , COVID-19/metabolism , Drug Discovery , Estrogen Antagonists/pharmacology , Female , Humans , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Receptors, Androgen/analysis , Receptors, Androgen/metabolism , Serine Endopeptidases/analysis , Serine Endopeptidases/metabolism , Signal Transduction/drug effects , Tamoxifen/pharmacology
8.
Arch Med Res ; 52(1): 48-57, 2021 01.
Article in English | MEDLINE | ID: covidwho-893598

ABSTRACT

BACKGROUND: Ras-GTPase activating protein SH3-domain-binding proteins (G3BP) are a small family of RNA-binding proteins implicated in regulating gene expression. Changes in expression of G3BPs are correlated to several cancers including thyroid, colon, pancreatic and breast cancer. G3BPs are important regulators of stress granule (SG) formation and function. SG are ribonucleoprotein (RNP) particles that respond to cellular stresses to triage mRNA resulting in transcripts being selectively degraded, stored or translated resulting in a change of gene expression which confers a survival response to the cell. These changes in gene expression contribute to the development of drug resistance. Many RNA viruses, including Chikungunya (and potentially Coronavirus), dismantle SG so that the cell cannot respond to the viral infection. Non-structural protein 3 (nsP3), from the Chikungunya virus, has been shown to translocate G3BP away from SG. Interestingly in cancer cells, the formation of SG is correlated to drug-resistance and blocking SG formation has been shown to reestablish the efficacy of the anticancer drug bortezomib. METHODS: Chikungunya nsP3 was transfected into breast cancer cell lines T47D and MCF7 to disrupt SG formation. Changes in the cytotoxicity of bortezomib were measured. RESULTS: Bortezomib cytotoxicity in breast cancer cell lines changed with a 22 fold decrease in its IC50 for T47D and a 7 fold decrease for MCF7 cells. CONCLUSIONS: Chikungunya nsP3 disrupts SG formation. As a result, it increases the cytotoxicity of the FDA approved drug, bortezomib. In addition, the increased cytotoxicity appears to correlate to improved bortezomib selectivity when compared to control cell lines.


Subject(s)
Bortezomib/pharmacology , Chikungunya Fever/drug therapy , Chikungunya virus/genetics , Cytoplasmic Granules/metabolism , DNA Helicases/metabolism , Poly-ADP-Ribose Binding Proteins/metabolism , RNA Helicases/metabolism , RNA Recognition Motif Proteins/metabolism , Viral Nonstructural Proteins/metabolism , Animals , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Chikungunya Fever/metabolism , Chikungunya Fever/pathology , Chikungunya virus/metabolism , Chlorocebus aethiops , Cytoplasmic Granules/drug effects , Cytoplasmic Granules/pathology , DNA Helicases/genetics , Down-Regulation , Drug Resistance, Neoplasm , Female , HEK293 Cells , HeLa Cells , Humans , MCF-7 Cells , Poly-ADP-Ribose Binding Proteins/genetics , RNA Helicases/genetics , RNA Recognition Motif Proteins/genetics , Transfection , Vero Cells , Viral Nonstructural Proteins/administration & dosage , Viral Nonstructural Proteins/genetics
9.
Breast Cancer Res Treat ; 184(2): 637-647, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-716322

ABSTRACT

PURPOSE: The COVID-19 pandemic has impacted early breast cancer (EBC) treatment worldwide. This study analyzed how Brazilian breast specialists are managing EBC. METHODS: An electronic survey was conducted with members of the Brazilian Society of Breast Cancer Specialists (SBM) between April 30 and May 11, 2020. Bivariate analysis was used to describe changes in how specialists managed EBC at the beginning and during the pandemic, according to breast cancer subtype and oncoplastic surgery. RESULTS: The response rate was 34.4% (503/1462 specialists). Most of the respondents (324; 64.4%) lived in a state capital city, were board-certified as breast specialists (395; 78.5%) and either worked in an academic institute or one associated with breast cancer treatment (390; 77.5%). The best response rate was from the southeast of the country (240; 47.7%) followed by the northeast (128; 25.4%). At the beginning of the pandemic, 43% changed their management approach. As the outbreak progressed, this proportion increased to 69.8% (p < 0.001). The southeast of the country (p = 0.005) and the state capital cities (p < 0.001) were associated with changes at the beginning of the pandemic, while being female (p = 0.001) was associated with changes during the pandemic. For hormone receptor-positive tumors with the best prognosis (Ki-67 < 20%), 47.9% and 17.7% of specialists would recommend neoadjuvant endocrine therapy for postmenopausal and premenopausal women, respectively. For tumors with poorer prognosis (Ki-67 > 30%), 34% and 10.9% would recommend it for postmenopausal and premenopausal women, respectively. Menopausal status significantly affected whether the specialists changed their approach (p < 0.00001). For tumors ≥ 1.0 cm, 42.9% of respondents would recommend neoadjuvant systemic therapy for triple-negative tumors and 39.6% for HER2 + tumors. Overall, 63.4% would recommend immediate total breast reconstruction, while only 3.4% would recommend autologous reconstruction. In breast-conserving surgery, 75% would recommend partial breast reconstruction; however, 54.1% would contraindicate mammoplasty. Furthermore, 84.9% of respondents would not recommend prophylactic mastectomy in cases of BRCA mutation. CONCLUSIONS: Important changes occurred in EBC treatment, particularly for hormone receptor-positive tumors, as the outbreak progressed in each region. Systematic monitoring could assure appropriate breast cancer treatment, mitigating the impact of the pandemic.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/therapy , Coronavirus Infections , Mammaplasty , Mastectomy , Neoadjuvant Therapy , Pandemics , Pneumonia, Viral , Adult , Betacoronavirus , Brazil , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , COVID-19 , Delivery of Health Care , Disease Management , Female , Genes, BRCA1 , Genes, BRCA2 , Humans , Male , Mastectomy, Segmental , Middle Aged , Patient Selection , Postmenopause , Premenopause , Prophylactic Mastectomy , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , SARS-CoV-2 , Societies, Medical , Surveys and Questionnaires , Tumor Burden
11.
Breast Cancer Res Treat ; 182(3): 515-521, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-593582

ABSTRACT

PURPOSE: Cryoablation is a minimally-invasive percutaneous procedure that is capable of reducing the psychosocial burden of surgical delay while also decreasing the morbidity of breast cancer therapy. The purpose of this editorial is to discuss the potential role of cryoablation for reducing the psychosocial burden of surgical delay during the COVID-19 pandemic by expediting the management of breast cancer while also lessening demand on limited healthcare resources. METHODS: This editorial critiques current expert opinion recommendations that aim to reduce viral transmission and preserve healthcare resources during the COVID-19 pandemic by advocating delay of elective breast cancer surgery. RESULTS: The editorial summarizes the current state of the evidence that supports the selective use of cryoablation as a definite or stopgap measure in the management of breast cancer during the COVID-19 pandemic or when healthcare resources are limited. CONCLUSIONS: As an office-based procedure performed under local anesthesia, cryoablation eliminates the need for operating room personnel and equipment while also reducing the psychosocial impact of delayed breast cancer surgery. By reducing the number of patient and healthcare provider interactions, cryoablation not only decreases the risk of viral transmission but also the need for personal protective devices during resource-limited times.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Anxiety/psychology , Breast Neoplasms/therapy , Coronavirus Infections/epidemiology , Cryosurgery/methods , Mastectomy , Neoadjuvant Therapy , Pneumonia, Viral/epidemiology , Time-to-Treatment , Ambulatory Surgical Procedures , Betacoronavirus , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/psychology , COVID-19 , Coronavirus Infections/prevention & control , Female , Humans , Mastectomy, Segmental , Neoplasm Staging , Pandemics/prevention & control , Personal Protective Equipment/supply & distribution , Pneumonia, Viral/prevention & control , Risk Assessment , SARS-CoV-2
12.
Cells ; 9(6)2020 05 27.
Article in English | MEDLINE | ID: covidwho-618482

ABSTRACT

The renin-angiotensin system (RAS) is a network of proteins regulating many aspects of human physiology, including cardiovascular, pulmonary, and immune system physiology. The RAS is a complicated network of G-protein coupled receptors (GPCRs) (i.e., AT1R, AT2R, MASR, and MRGD) orchestrating the effects of several hormones (i.e., angiotensin II, angiotensin (1-7), and alamandine) produced by protease-based transmembrane receptors (ACE1 and ACE2). Two signaling axes have been identified in the RAS endocrine system that mediate the proliferative actions of angiotensin II (i.e., the AT1R-based pathway) or the anti-proliferative effects of RAS hormones (i.e., the AT2R-, MAS-, and MRGD-based pathways). Disruption of the balance between these two axes can cause different diseases (e.g., cardiovascular pathologies and the severe acute respiratory syndrome coronavirus 2- (SARS-CoV-2)-based COVID-19 disease). It is now accepted that all the components of the RAS endocrine system are expressed in cancer, including cancer of the breast. Breast cancer (BC) is a multifactorial pathology for which there is a continuous need to identify novel drugs. Here, I reviewed the possible roles of both axes of the RAS endocrine network as potential druggable pathways in BC. Remarkably, the analysis of the current knowledge of the different GPCRs of the RAS molecular system not only confirms that AT1R could be considered a drug target and that its inhibition by losartan and candesartan could be useful in the treatment of BC, but also identifies Mas-related GPCR member D (MRGD) as a druggable protein. Overall, the RAS of GPCRs offers multifaceted opportunities for the development of additional compounds for the treatment of BC.


Subject(s)
Breast Neoplasms/metabolism , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/metabolism , Renin-Angiotensin System , Angiotensin I/metabolism , Angiotensin II/metabolism , Female , Humans , Peptide Fragments/metabolism , Proto-Oncogene Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism
13.
J Natl Cancer Inst ; 113(4): 355-359, 2021 04 06.
Article in English | MEDLINE | ID: covidwho-361366

ABSTRACT

Caring for older patients with breast cancer presents unique clinical considerations because of preexisting and competing comorbidity, the potential for treatment-related toxicity, and the consequent impact on functional status. In the context of the COVID-19 pandemic, treatment decision making for older patients is especially challenging and encourages us to refocus our treatment priorities. While we work to avoid treatment delays and maintain therapeutic benefit, we also need to minimize the risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposures, myelosuppression, general chemotherapy toxicity, and functional decline. Herein, we propose multidisciplinary care considerations for the aging patient with breast cancer, with the goal to promote a team-based, multidisciplinary treatment approach during the COVID-19 pandemic and beyond. These considerations remain relevant as we navigate the "new normal" for the approximately 30% of breast cancer patients aged 70 years and older who are diagnosed in the United States annually and for the thousands of older patients living with recurrent and/or metastatic disease.


Subject(s)
Breast Neoplasms/therapy , COVID-19/prevention & control , Interdisciplinary Communication , Medical Oncology/methods , Aged , Aged, 80 and over , Breast Neoplasms/diagnosis , Breast Neoplasms/metabolism , COVID-19/epidemiology , COVID-19/virology , Female , Humans , Medical Oncology/statistics & numerical data , Neoplasm Metastasis/prevention & control , Neoplasm Recurrence, Local/prevention & control , Pandemics , Receptor, ErbB-2/metabolism , SARS-CoV-2/physiology , United States
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