scholarly journals In Vitro and in Silico Analysis of miR-125a with rs12976445 Polymorphism in Breast Cancer Patients

2020 ◽  
Vol 10 (20) ◽  
pp. 7275
Author(s):  
Tomasz P. Lehmann ◽  
Joanna Miskiewicz ◽  
Natalia Szostak ◽  
Marta Szachniuk ◽  
Sylwia Grodecka-Gazdecka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
In Silico ◽  
Growth Factor Receptor ◽  
In Silico Analysis ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Alternative Protein ◽  
Cancer Tissues

Background: Breast cancer affects over 2 million women yearly. Its early detection allows for successful treatment, which motivates to research factors that enable an accurate diagnosis. miR-125a is one of them, correlating with different types of cancer. For example, the miR-125a level decreases in breast cancer tissues; polymorphisms in the miR-125a encoding gene are related to prostate cancer and the risk of radiotherapy-induced pneumonitis. Methods: In this work, we investigated two variants of rs12976445 polymorphism in the context of breast cancer. We analyzed the data of 175 blood samples from breast cancer patients and compared them with the control data from 129 control samples. Results: We observed the tendency that in breast cancer cases TT genotype appeared slightly more frequent over CC and CT genotypes (statistically nonsignificant). The TT genotype appeared also to be more frequent among human epidermal growth factor receptor 2 (HER2) positive patients, compared to HER2 negative. In silico modelling showed that the presence of uridine (U) diminished the probability of pri-miR-125a binding to NOVA1 and HNRNPK proteins. We demonstrated that U and C -variants could promote different RNA folding patterns and provoke alternative protein binding. Conclusions: U-variant may imply a lower miR-125a expression in breast cancer.

Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

2021 ◽  
pp. 1-10
Author(s):  
Yu Wang ◽  
Han Zhao ◽  
Ping Zhao ◽  
Xingang Wang
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

scholarly journals CDK12 inhibition enhances sensitivity of HER2+ breast cancers to HER2-TKI via suppressing PI3K/AKT

2020 ◽  
Author(s):  
Hui Li ◽  
Jinsong Wang ◽  
Zongbi Yi ◽  
Chunxiao Li ◽  
Haijuan Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
High Throughput Sequencing ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Abstract Background : While anti-HER2 tyrosine kinase inhibitors (TKIs) have radically prolonged survival and improved prognosis in HER2-positive breast cancer patients, resistance to these therapies is a constant obstacle leading to TKIs treatment failure and tumor progression.Methods : To develop new strategies to enhance TKIs efficiency by combining synergistic gene targets, we performed panel library screening using CRISPR/Cas9 knockout technique based on data mining across TCGA datasets and verified the candidate target in pre-clinical models and breast cancer high-throughput sequencing datasets.Results : We identified that CDK12, co-amplified with HER2 in a high frequency, is powerful to sensitize or re-sensitize HER2-positive breast cancer to anti-HER2 TKIs lapatinib, evidenced by patient-derived organoids (PDO) in vitro and cell-derived xenograft (CDX) or patient-derived xenograft (PDX) in vivo. Exploring mechanisms, we found that inhibition of CDK12 attenuated PI3K/AKT signal, which usually serves as an oncogenic driver and is reactivated when HER2-positive breast cancers develop resistance to lapatinib. Combining CDK12 inhibition exerted additional suppression on p-AKT activation induced by anti-HER2 TKIs lapatinib treatment. Clinically, via DNA sequencing data for tumor tissue and peripheral blood ctDNA, we found that HER2-positive breast cancer patients with CDK12 amplification responded more insensitively to anti-HER2 treatment than those without accompanying CDK12 amplification by harboring a markedly shortened progression free survival (PFS) (median PFS: 4.3 months verse 6.9 months; HR 2.26 [95% CI 1.32-3.86]; P=0.0028).Conclusions : Dual inhibition of HER2/CDK12 will prominently benefit the outcomes of HER2-positive breast cancer patients by sensitizing or re-sensitizing the tumors to anti-HER2 TKIs treatment.

Tumor mutation burden and PIK3CA mutations are associated with pathological complete response in human epidermal growth factor receptor 2-positive breast cancer patients receiving pyrotinib combined with trastuzumab neoadjuvant treatment.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12610-e12610
Author(s):  
Qiyun Shi ◽  
Juncheng Xuhong ◽  
Jia Ge ◽  
Feng Liu ◽  
Yang Lan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Neoadjuvant Treatment ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Mutation Burden ◽  
Positive Breast Cancer

e12610 Background: Our previous study reported a good efficacy and safety of pyrotinib combined with trastuzumab neoadjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. We further explored the potential biomarkers for the efficacy of pyrotinib combined with trastuzumab neoadjuvant treatment in HER2-positive breast cancer patients. Methods: To date, a total of 96 patients with early-stage breast cancer were enrolled for the neoadjuvant pyrotinib combined with trastuzumab treatment clinical trial (ChiCTR1900022293). By the method of 425 genes next-generation sequencing (NGS), the genomic characteristics of them were evaluated for the potential correlation with postoperative pathological complete response (pCR). Results: Among the cohort of 96 cases, a total of 32 patients have completed the whole therapy as well as final surgery and acquired qualified sequencing analysis report, and 18 of them achieved total pCR. The most frequently mutated driver genes were TP53 (75%), PIK3CA (44%), NBN (9%), RUNX1 (9%), FANCD2 (9%), ATRX (9%), MAP3K1 (9%) and NF1 (9%), respectively. In terms of somatic copy number alterations, the most frequent alterations are gain or amplification of ERBB2 (63%), MYC (22%), CCND1 (19%), CDK12 (16%) and FGF19 (16%), respectively. The median tumor mutation burden (TMB) of the 36 patients was 4.23 mut/Mb (0.00-29.61). Compared with pCR populations, non-pCR populations had significantly higher median TMB (5.29 vs 3.17 mut/Mb, P = 0.025). In addition, the pCR rate of patients with wild-type PIK3CA is significantly higher than that of patients with mutated PIK3CA (88.9% vs 14.3%, P < 0.001). Conclusions: Preliminary results suggested that HER2-positive breast cancer patients with higher TMB and activating mutations in PIK3CA are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy, which need larger sample size to validate. *Qiyun Shi and Juncheng Xuhong contributed equally. #Co-corresponding author (Dr. Jun Jiang, [email protected]; Dr. Xiaowei Qi, [email protected]). Clinical trial information: ChiCTR1900022293.

Need for systematic de-escalation of care in HER2+ breast cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12657-e12657
Author(s):  
Tushar Pandey ◽  
Tyler M Earnest ◽  
John A Cole ◽  
Eduardo Braun
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Cancer Patients ◽  
In Silico ◽  
Treatment Plan ◽  
Standard Of Care ◽  
Her2 Status ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Breast Cancer

e12657 Background: Over the last decade, there has been incredible progress in HER2-positive breast cancer patients with the adoption of targeted therapies like Trastuzumab and Pertuzumab to complement existing chemotherapies. Increasingly neoadjuvant therapy is the preferred method of therapy as it is better able to predict prognosis via pCR as well as guide adjuvant therapeutic strategy in cases with residual tumor. There are now a variety of combination therapies recommended for HER2-positive patients. As new therapies are developed, the standard-of-care shifts towards the regimen with highest pCR rate. The latest regimen being TCHP which produced pCR rates over 60% in clinical trials. While the improvement in pCR rates at a population level is encouraging, there is a growing sentiment among physicians that we may be over treating patients impacting both costs and resulting toxicity. Methods: We performed an analysis of Breast Cancer trials with pCR as the primary end point and stratification available based on HER2+ status. The cost (median insurance reimbursement) was also referenced from a recent ASCO observational study as a proxy for direct costs of drugs. Toxicities were referenced and each regimen scored (TS) from NCCN Evidence Blocks and adverse events from clinical trials. Potential savings were evaluated if a clinician had the ability to individualize regimen choice by patient. We utilized the SimBioSys TumorScope platform to perform in silico simulations to predict response to alternate therapies as it had previously used to analyze potential deescalate between AC-T vs TC in a HER2- cohort. Results: The following regimens were evaluated HP (pCR:17%,TS:1), TH (pCR: 29%,TS: 2) THP (pCR: 46%, TS: 3), TCH (pCR: 43%, TS: 4), TCHP (pCR: 64%, TS: 5), AC-TH (pCR: 43%, TS: 6), AC-THP(pCR: 55%, TS: 7). Based on an in-silico analysis and selection (where pCR was likely with multiple regimens), the lowest cost & toxicity regimen was selected. The estimated average saving per case of over $100,000 for the overall treatment plan . The calculated toxicity score was also reduced by this method to under 4 from the TCHP(5) standard of care. Conclusions: While the results above are estimates and perfection in such individualization may not be possible, an in-silico approach provides a promising solution.

scholarly journals Expression of Alpha-Enolase (ENO1), Myc Promoter-Binding Protein-1 (MBP-1) and Matrix Metalloproteinases (MMP-2 and MMP-9) Reflect the Nature and Aggressiveness of Breast Tumors

2019 ◽  
Vol 20 (16) ◽  
pp. 3952 ◽  
Author(s):  
Patrizia Cancemi ◽  
Miriam Buttacavoli ◽  
Elena Roz ◽  
Salvatore Feo
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Matrix Metalloproteinases ◽  
Cancer Patients ◽  
Binding Protein ◽  
Hypoxia Tolerance ◽  
Activity Levels ◽  
Breast Cancer Patients ◽  
Cancer Tissues

Breast cancer is a complex and heterogeneous disease: Several molecular alterations cause cell proliferation and the acquisition of an invasive phenotype. Extracellular matrix (ECM) is considered essential for sustaining tumor growth and matrix metalloproteinases (MMPs) have been identified as drivers of many aspects of the tumor phenotype. Mounting evidence indicates that both α-enolase (ENO1) and Myc promoter-binding protein-1 (MBP-1) also played pivotal roles in tumorigenesis, although as antagonists. ENO1 is involved in cell growth, hypoxia tolerance and autoimmune activities besides its major role in the glycolysis pathway. On the contrary, MBP-1, an alternative product of ENO1, suppresses cell proliferation and the invasive ability of cancer cells. Since an important task in personalized medicine is to discriminate a different subtype of patients with different clinical outcomes including chances of recurrence and metastasis, we investigated the functional relationship between ENO1/MBP-1 expression and MMP-2 and MMP-9 activity levels in both tissues and sera of breast cancer patients. We focused on the clinical relevance of ENO1 and MMPs (MMP-2 and MMP-9) overexpression in breast cancer tissues: The association between the higher ENO1, MMP-2 and MMP-9 expression with a worse prognosis suggest that the elevated ENO1 and MMPs expression are promising biomarkers for breast cancer. A relationship seems to exist between MBP-1 expression and the decrease in the activity levels of MMP-9 in cancer tissues and MMP-2 in sera. Moreover, the sera of breast cancer patients grouped for MBP-1 expression differentially induced, in vitro, cell proliferation and migration. Our findings support the hypothesis of patient’s stratification based on ENO1, MBP-1 and MMPs expression. Elucidating the molecular pathways through which MBP-1 influences MMPs expression and breast cancer regression can lead to the discovery of new management strategies.

scholarly journals ANTI-HER2 ANTIBODIES IN COMBINATION WITH CHEMOTHERAPY OR CHEMOTHERAPY-FREE REGIMENS TARGETING HER2-POSITIVE BREAST CANCER: A SYSTEMATIC REVIEW

2020 ◽  
Vol 20 (2) ◽  
pp. 285-306
Author(s):  
Siti Muhamad Nur Husna ◽  
Faezahtul Arbaeyah Hussain ◽  
Maya Mazuwin Yahya ◽  
Anne Dyhl-Polk ◽  
Kah Keng Wong
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Cancer Patients ◽  
Growth Factor Receptor ◽  
Therapeutic Antibodies ◽  
Breast Cancer Patients ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Breast cancer is the leading cause of cancer-related death in female worldwide. Human epidermal growth factor receptor 2 (HER2) amplification is observed in approximately 20% of breast cancer cases and is associated with poor clinical outcomes. Dual HER2 blockade without chemotherapy represents an attractive therapeutic approach, and it remains unresolved if anti-HER2 therapeutic antibodies are sufficient to replace chemotherapy regimens. In this review, we discuss the approved therapeutic monoclonal antibodies (pertuzumab and trastuzumab) and antibody-drug conjugate (trastuzumab emtansine or T-DM1) for the treatment of HER2-positive breast cancer patients. In summary, phase II and III clinical trials have demonstrated that dual HER2 blockade (pertuzumab and trastuzumab) plus chemotherapy regimens confer better efficacy compared with dual HER2 blockade alone, or anti-HER2 antibody monotherapy, in HER2-positive breast cancer patients. Dual HER2 blockade (pertuzumab and trastuzumab) combined with chemotherapies (5-fluorouracil, epirubicin, cyclophosphamide and docetaxel) yield superior response. Moreover, dual HER2 blockade (T-DM1 and pertuzumab) in combination with docetaxel represents a promising treatment regimen containing T-DM1. Ongoing clinical trials are assessing the optimal chemotherapy of choice with anti-HER2 antibodies combinations. In conclusion, improved outcomes are attributable to selection for the optimal chemotherapy regimen in combination with anti-HER2 antibodies instead of replacing chemotherapy altogether with the current line of anti-HER2 therapeutic antibodies.

Flaxseed and its lignan and oil components: can they play a role in reducing the risk of and improving the treatment of breast cancer?

2014 ◽  
Vol 39 (6) ◽  
pp. 663-678 ◽  
Author(s):  
Julie K. Mason ◽  
Lilian U. Thompson
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Cancer Patients ◽  
Tumour Growth ◽  
Growth Factor Receptor ◽  
Premenopausal Women ◽  
Estrogen Metabolism ◽  
Breast Cancer Patients ◽  
Oil Components

Flaxseed (FS), rich in the phytoestrogen lignans and α-linolenic acid-rich oil, has been suggested to have an anticancer effect. Questions remain whether FS and its lignan and oil components are effective in reducing breast cancer risk and tumour growth, and can interact beneficially with breast cancer drugs. To find answers, in vitro, animal, observational, and clinical studies on FS and its lignan and oil components were reviewed. The majority of studies in various rodent models show that 2.5%–10% FS diet or the equivalent amount of lignan or oil reduces tumour growth. Ten percent FS and equivalent lignans do not interfere with but rather increase the effectiveness of tamoxifen (80 mg/day) while the 4% FS oil increases trastuzumab/Herceptin (2.5 mg/kg) effectiveness. Observational studies show that FS and lignan intake, urinary excretion, or serum levels are associated with reduced risk, particularly in postmenopausal women. Lignans reduce breast cancer and all-cause mortality by 33%–70% and 40%–53%, respectively, without reducing tamoxifen effectiveness. Clinical trials show that FS (25 g/day with 50 mg lignans; 32 days) reduces tumour growth in breast cancer patients and lignans (50 mg/day; 1 year) reduces risk in premenopausal women. Mechanisms include decreased cell proliferation and angiogenesis and increased apoptosis through modulation of estrogen metabolism and estrogen receptor and growth factor receptor signalling pathways. More clinical trials are needed but current overall evidence indicates that FS and its components are effective in the risk reduction and treatment of breast cancer and safe for consumption by breast cancer patients.

scholarly journals Study of Receptor Status in Carcinoma Breast Patient

2018 ◽  
Vol 16 (2) ◽  
pp. 48-50 ◽  
Author(s):  
Shakera Ahmed ◽  
Khondker AK Azad
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Receptor Status ◽  
Background Estimation ◽  
Epidermal Growth ◽  
The Cost

Background: Estimation of Estrogen Receptor (ER) Progesterone Receptor (PR) and Human Epidermal Growth Factor Receptor 2 (HER2) is mandatory for choosing treatment options and prognosis of breast cancer patients. This estimation can be done by Immunohistochemistry (IHC) and Fluoroscence In Situ Hybridization (FISH) test. As the tests are expensive many of our patients can’t afford to do it. But if we practice doing the test routinely the cost will be reduced and our patients will be benefited. So we underwent a primitive study on receptor status in breast cancer patients. Our goal was to encourage the surgeons to advice receptor status routinely and treat the patients accordingly as patients prognosis will be much more better if they are treated according to their receptor status.Methods: This was a retrospective observational study of 74 breast cancer patients in a private clinic. In this study we have shown their receptor status by IHC and the data were analyzed.Results: Among the 74 patients 32 were ER +ve PR +ve, 11 were ER +ve PR -ve, 02 were ER –ve PR +ve, 29 were ER -ve PR -ve. ER &/or PR positive patients will be more responsive to hormone therapy. 28 patients were HER2 +ve, 34 patients were HER2 –ve and 9 were equivocal. HER2 positive patients will be benefited from targeted therapy. Among the patients 11 were triple negative that means they have worst prognosis.Conclusion: As knowing the receptor status in breast cancer help us as a predictive, prognostic and therapeutic indicator, we must advice it routinely and take steps to make it cheaper and easily available.Chatt Maa Shi Hosp Med Coll J; Vol.16 (2); July 2017; Page 48-50

scholarly journals Let-7d Inhibits Growth and Metastasis in Breast Cancer by Targeting Jab1/Cops5

2018 ◽  
Vol 47 (5) ◽  
pp. 2126-2135 ◽  
Author(s):  
Yongchang Wei ◽  
Guohong Liu ◽  
Balu Wu ◽  
Yufen Yuan ◽  
Yunbao Pan
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Tumor Development ◽  
Luciferase Reporter ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
In Vivo Experiments ◽  
Cancer Tissues

Background/Aims: MicroRNAs (miRNAs) regulate the expressions of cancer-related genes, and are involved in the development and progression of various human cancers. Here, we performed further analyses to determine whether let-7d is functionally linked to Jab1 in breast cancer. Methods: In situ hybridization and immunohistochemical analyses were used to determine the level of let-7d and Jab1 in breast cancer clinical specimens and its correlation with clinicopathological data. Let-7d overexpressing breast cancer cell lines combined with mouse models bearing cell-derived xenografts were used to assess the functional role of let-7d both in vitro and in vivo. Results: In this study, we found that let-7d was downregulated in breast cancer tissues, coupled with the elevations of Jab1 protein expressions, compared with paired adjacent noncancerous breast tissues. Let-7d overexpression significantly suppressed the proliferation and invasion in MCF-7 and MDA-MB-231 cells. Dual luciferase reporter assay indicated that Jab1 was the direct target of let-7d. Stepwise studies from in vitro and in vivo experiments indicated that let-7d overexpression inhibited cell growth and decreased Jab1 expressions in breast cancer cells and nude mice tumor tissues. Statistical analyses demonstrated that breast cancer patients with low levels of let-7d or high levels of Jab1 had a significant correlation with worse prognosis. Conclusion: These findings provide novel insights into molecular mechanism of let-7d and Jab1 in tumor development and progression of breast cancer, and thus let-7d/Jab1 are novel potential therapeutic targets for breast cancer patients.

Treatment outcomes among human epidermal growth factor receptor 2 positive breast cancer patients: A systematic review

2021 ◽  
pp. 107815522110055
Author(s):  
Amsalu Degu ◽  
Asha Yussuf
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Treatment Outcomes ◽  
Cancer Patients ◽  
Growth Factor Receptor ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Her 2 ◽  
Positive Breast Cancer

Background The incidence of human epidermal growth factor receptor 2 (HER 2) positive breast cancers is rapidly rising worldwide. Although there have been many studies on HER 2 breast cancer treatment and management in recent years, there is a lack of comprehensive reports on the treatment outcomes and disparities within the available literature. Hence, this review aimed to determine the treatment outcomes and their associated factors among patients with HER2-positive breast cancer. Methods A computer-based systematic literature search was conducted using PubMed, EMBASE, and Google scholar databases of articles published from 2000 to 2020. The following key terms (HER 2 positive breast cancer, predictor, determinant, associated factor) and Medical Subject Headings (MeSH) terms (breast neoplasms, treatment outcome, and risk factors) were used to search the English language published articles. Results In most studies, trastuzumab was the most commonly used treatment regimen used in combination with chemotherapeutic agents. Generally, most of the studies (15 studies) showed that the overall survival outcome was relatively higher after treatment among HER2 positive breast cancer patients. Nonetheless, two studies showed that the absence of significant change in the overall survival despite adequate treatment was given to the study participants. In addition, three studies demonstrated a partial response after treating HER2-positive breast cancer patients. Conclusion Generally, the overall survival outcome was relatively higher after treatment among HER2 positive breast cancer patients. The addition of trastuzumab in most of the studies has shown improvement in the overall survival and the disease-free survival rate of the study patients.

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