scholarly journals The PI3K Pathway: Background and Treatment Approaches

Breast Care ◽  
2016 ◽  
Vol 11 (6) ◽  
pp. 398-404 ◽  
Author(s):  
Michael P. Lux ◽  
Peter A. Fasching ◽  
Michael G. Schrauder ◽  
Alexander Hein ◽  
Sebastian M. Jud ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Tamoxifen Treatment ◽  
Breast Cancer Patients ◽  
Secondary Resistance ◽  
Treatment Approaches ◽  
Metastatic Breast Carcinoma ◽  
Promising Therapeutic Approach

Two-thirds of all breast cancer patients with metastases have a hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative subtype. Endocrine therapy is the treatment of choice in these patients since in addition to its effectiveness it can also maintain the patients' quality of life over a longer term. However, 44-62% of postmenopausal patients with metastatic breast carcinoma have primary tamoxifen resistance. After 3-5 years, 30-40% of the patients receiving tamoxifen treatment develop secondary resistance. Understanding the way in which resistance develops is therefore essential for developing treatment approaches that can prevent or reverse endocrine resistance. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role here. As a result of the numerous interactions involved, complex issues arise that need to be taken into account in the development and use of therapeutic agents. In addition, this signaling pathway is the one that most frequently undergoes mutations in breast cancer. The prognostic and predictive significance of individual mutations has not yet been fully explained, but it might provide a basis for patient selection in clinical studies. Initial research results on the use of PI3K inhibitors suggest that this may be a highly promising therapeutic approach, with an acceptable side effect profile.

Prognostic Role of Hedgehog-GLI1 Signaling Pathway in Aggressive and Metastatic Breast Cancers

2020 ◽  
Vol 21 (1) ◽  
pp. 33-43 ◽  
Author(s):  
Prasuja Rokkam ◽  
Shailender Gugalavath ◽  
Deepak Kakara Gift Kumar ◽  
Rahul Kumar Vempati ◽  
Rama Rao Malla
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Neural Development ◽  
Splice Variants ◽  
Metastatic Breast ◽  
Basic Function ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Aberrant Expression ◽  
Cellular Processes

Glioma-associated oncogene homolog 1 (GLI1) is reported as an amplified gene in human glioblastoma cells. It is a krupple like transcription factor, belonging to the zinc finger family. The basic function of GLI1 is normal neural development at various stages of human. The GLI1 gene was first mapped on the chromosome sub-bands 12q13.3-14.1. Further, single nucleotide polymorphism is mostly observed in translating a region of 5’ and 3’- UTR of GLI1 gene in addition to two post-transcriptional splice variants, GLIΔN and tGLI. Additionally, it also regulates a plethora of gene which mediates crucial cellular processes like proliferation, differentiation, oncogenesis, EMT, and metastasis. It also regulates tumor tolerance, chemoresistance, and radioresistance. Aberrant expression of GLI1 predicts the poor survival of breast cancer patients. GLI1 is an essential mediator of the SHH signaling pathway regulating self-renewal of stem cells, angiogenesis, and expression of FOXS1, CYR61. GLI1 mediated HH pathway can induce apoptosis. Hence, GLI1 can be a future diagnostic, prognostic marker, and as well as a potent target of therapeutics in breast cancer.

scholarly journals Quercetin Inhibits Lef1 and Resensitizes Docetaxel-Resistant Breast Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2576 ◽  
Author(s):  
Marta Prieto-Vila ◽  
Iwao Shimomura ◽  
Akiko Kogure ◽  
Wataru Usuba ◽  
Ryou-u Takahashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Metastatic Breast ◽  
Drug Resistant ◽  
Breast Cancer Patients ◽  
Phase I Clinical Trials ◽  
Pathway Activation ◽  
Promising Therapeutic Approach ◽  
Cav1 Expression ◽  
Resistant Cells

Drug resistance is a major problem for breast cancer patients. Docetaxel is an anti-mitotic agent that serves as first line of treatment in metastatic breast cancer, however it is susceptible to cellular drug resistance. Drug-resistant cells are able to spread during treatment, leading to treatment failure and eventually metastasis, which remains the main cause for cancer-associated death. In previous studies, we used single-cell technologies and identified a set of genes that exhibit increased expression in drug-resistant cells, and they are mainly regulated by Lef1. Furthermore, upregulating Lef1 in parental cells caused them to become drug resistant. Therefore, we hypothesized that inhibiting Lef1 could resensitize cells to docetaxel. Here, we confirmed that Lef1 inhibition, especially on treatment with the small molecule quercetin, decreased the expression of Lef1 and resensitized cells to docetaxel. Our results demonstrate that Lef1 inhibition also downregulated ABCG2, Vim, and Cav1 expression and equally decreased Smad-dependent TGF-β signaling pathway activation. Likewise, these two molecules worked in a synergetic manner, greatly reducing the viability of drug-resistant cells. Prior studies in phase I clinical trials have already shown that quercetin can be safely administered to patients. Therefore, the use of quercetin as an adjuvant treatment in addition to docetaxel for the treatment of breast cancer may be a promising therapeutic approach.

scholarly journals AGR2 Predicts Tamoxifen Resistance in Postmenopausal Breast Cancer Patients

2013 ◽  
Vol 35 ◽  
pp. 207-212 ◽  
Author(s):  
Roman Hrstka ◽  
Veronika Brychtova ◽  
Pavel Fabian ◽  
Borivoj Vojtesek ◽  
Marek Svoboda
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Optimal Algorithm ◽  
Endocrine Resistance ◽  
Postmenopausal Breast Cancer ◽  
Progression Free Survival ◽  
Tamoxifen Treatment ◽  
Mrna Levels ◽  
Breast Cancer Patients ◽  
Er Positive

Endocrine resistance is a significant problem in breast cancer treatment. Thus identification and validation of novel resistance determinants is important to improve treatment efficacy and patient outcome. In our work, AGR2 expression was determined by qRT-PCR in Tru-Cut needle biopsies from tamoxifen-treated postmenopausal breast cancer patients. Our results showed inversed association of AGR2 mRNA levels with primary treatment response (P=0.0011) and progression-free survival (P=0.0366) in 61 ER-positive breast carcinomas. As shown by our experimental and clinical evaluations, elevated AGR2 expression predicts decreased efficacy of tamoxifen treatment. From this perspective, AGR2 is a potential predictive biomarker enabling selection of an optimal algorithm for adjuvant hormonal therapy in postmenopausal ER-positive breast cancer patients.

scholarly journals Liquid Biopsy: New Tool to Overcome CDKi Resistance Mechanism in Luminal Metastatic Breast Cancer

2021 ◽  
Author(s):  
Miriam González-Conde ◽  
Celso Yanez ◽  
Rafael López-López ◽  
Clotilde Costa
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Hormone Receptors ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Luminal Breast Cancer ◽  
Breast Cancer Patients ◽  
Her2 Breast Cancer

Breast cancer is the most commonly diagnosed cancer in women worldwide. Approximately, 70 % of breast cancer patients express hormone receptors (HR) (Luminal subtype). Adjuvant endocrine treatments are the standard of care in HR+/HER2- breast cancer. Over time, about 50% of those patients develop endocrine resistance and metastatic breast cancer. Cyclin-dependent kinase inhibitors (CDKi) in combination with an aromatase inhibitor or fulvestrant have demonstrated superior efficacy increasing progression-free survival, with a safe toxicity profile, in HR+/HER2- metastatic breast cancer patients. CDKi blocks kinases 4/6 ATP-binding domain preventing G1/S cell cycle transition. Despite this, not all patients respond to CDKi and those who respond, finally develop resistance to combination therapy. Different studies, in tumour tissue or cell lines, have tried to elucidate the mechanisms underlying this progression, but there are still no conclusive data. In the last few years, liquid biopsy has contributed relevant information to this knowledge. Liquid biopsy can be performed in real-time, non-invasively and be repeated whenever needed. Circulating tumour material are potential prognostic markers in metastatic luminal breast cancer to determine patient prognosis, monitor disease and treatment selection. The objective of this review is to outline the different studies carried out in HR+ metastatic breast cancer patients treated with CDKi plus endocrine therapy using liquid biopsy approaches looking for possible resistance mechanisms.

Plasma PIK3CA Mutation Testing in Advanced Breast Cancer Patients for Personalized Medicine: A Value Proposition

2020 ◽  
Vol 5 (5) ◽  
pp. 1076-1089
Author(s):  
Andrea Ferreira-Gonzalez
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Cancer Patients ◽  
Pik3ca Mutation ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Value Proposition ◽  
Breast Cancer Patients ◽  
A Value

Abstract Background Even though endocrine therapy is often initially successful in treating advanced breast cancer, most patients inevitably face disease progression. In advanced hormone receptor–positive (HR+) breast cancer, activation of the PI3K downstream pathway is a critical feature of the mechanism of endocrine resistance. A significant recent advance in treating HR+ advanced breast cancer has been the recent introduction of PI3K inhibitor (PI3Ki) for the treatment of patients with HR+, HER2-negative (HER2−) advanced or metastatic breast cancer that harbors PIK3CA mutations. A value proposition concept was applied to assess the potential benefits of cell-free tumor DNA (ctDNA) testing to identify patients who might respond to PI3Ki treatment. Content By applying the framework of the value proposition to >35 publications, in addition to recommendations from professional organizations, it was evident that robust clinical evidence exists to support the role of ctDNA PIK3CA mutation evaluation in identifying patients with advanced breast cancer who could benefit from PI3Ki treatment. Summary Detection of PIK3CA gene mutations in HR+HER2− advanced breast cancer patients allows for the identification of patients who might benefit from more effective personalized treatment with molecularly targeted drugs.

Impact of breast cancer chemotherapy on ovarian damage and recovery.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e24059-e24059
Author(s):  
Shari Beth Goldfarb ◽  
Giuliano Bedoschi ◽  
Volkan Turan ◽  
Angelena Crown ◽  
Nadia Abdo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Reserve ◽  
Metastatic Breast ◽  
Fold Increase ◽  
Important Predictor ◽  
Tamoxifen Treatment ◽  
Breast Cancer Patients ◽  
Breast Cancer Chemotherapy ◽  
Future Fertility ◽  
Extent Of Damage

e24059 Background: As societal shifts have led to more women delaying childbearing, a diagnosis of breast cancer is increasingly more likely to occur prior to the completion of family building. Therefore, understanding impact of chemo on future fertility is of the utmost importance. This study evaluates the trends in AMH over time in women receiving different chemo regimens for breast cancer. Methods: This is an IRB approved prospective study of 164 women, < 45 years old with non-metastatic breast cancer who were enrolled at time of diagnosis. Patients received chemo and had prospective serum AMH measured at baseline,12, 18 & 24 mos post-chemo. Of those, 99/164 completed 2-yr follow up. Pts were divided according to their chemotherapy regimen: ddAC-T, CMF and other (e.g. TH). Results: Mean age in ddAC-T (n = 118), CMF (n = 22) and other (n = 23) chemo groups were 37.1±4.6, 41.1±3.2 and 37.6±4.3 yrs, respectively (p = 0.001). AMH sharply declined between baseline & 12 mos post-chemo in all groups (p = 0.005). There was no difference in rate of decline between the groups, after adjusting for age. Age was an important predictor of AMH. Older age at study entry was associated with lower AMH with a decrease of 9% per life year (p = 0.0005). AMH recovered from 12 to 18 mos post-chemo in all groups. 18 mos after chemo, AMH recovery was observed in 61%, 59% & 65% in ddAC-T, CMF & other groups, respectively. In the ddAC-T arm there was a 1.9 fold increase in AMH while there was a 1.4 and 3.3 fold increase in the CMF and other arms, respectively. At 2-yrs post-chemo, AMH recovery rate reached 67%, 69% & 77% in ddAC-T, CMF & other groups, respectively. However, 12% in ddAC-T and 23% in CMF had undetectable AMH. Baseline AMH was 1.59 fold higher in pts whose AMH increased compared to those whose AMH decreased between 12 & 18 mos (p = 0.035). AMH recovery was associated with higher baseline AMH. Age, BMI & chemo type did not correlate with AMH recovery and tamoxifen treatment did not impact AMH recovery. Conclusions: Our data show that anthracycline plus taxane, taxane-based and CMF chemo regimens compromise ovarian reserve in breast cancer patients in similar fashion. As surviving ovarian follicles resume production of AMH, most of ovarian reserve recovery occurs by 18 mos post-chemo with some minor recovery from 18-24 mos. Baseline AMH level is the most important predictor of AMH recovery. Hence in women undergoing gonadotoxic chemo, ovarian reserve should be assessed by AMH before and 12 months after treatment to determine extent of damage. The novel information provided in this study is valuable for counseling cancer pts about fertility preservation. Clinical trial information: NCT00823654 .

scholarly journals Comparison of two targeted ultra-deep sequencing technologies for analysis of plasma circulating tumour DNA in endocrine-therapy-resistant breast cancer patients

2021 ◽  
Author(s):  
Georgios Nteliopoulos ◽  
Karen Page ◽  
Allison Hills ◽  
Karen Howarth ◽  
Warren Emmett ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Predictive Biomarker ◽  
Plasma Samples ◽  
Breast Cancer Patients ◽  
Sequencing Technologies ◽  
Highly Correlated ◽  
Detection Of Mutations ◽  
Circulating Tumour Dna

Abstract Purpose There is growing interest in the application of circulating tumour DNA (ctDNA) as a sensitive tool for monitoring tumour evolution and guiding targeted therapy in patients with cancer. However, robust comparisons of different platform technologies are still required. Here we compared the InVisionSeq™ ctDNA Assay with the Oncomine™ Breast cfDNA Assay to assess their concordance and feasibility for the detection of mutations in plasma at low (< 0.5%) variant allele fraction (VAF). Methods Ninety-six plasma samples from 50 patients with estrogen receptor (ER)-positive metastatic breast cancer (mBC) were profiled using the InVision Assay. Results were compared to the Oncomine assay in 30 samples from 26 patients, where there was sufficient material and variants were covered by both assays. Longitudinal samples were analysed for 8 patients with endocrine resistance. Results We detected alterations in 59/96 samples from 34/50 patients analysed with the InVision assay, most frequently affecting ESR1, PIK3CA and TP53. Complete or partial concordance was found in 28/30 samples analysed by both assays, and VAF values were highly correlated. Excellent concordance was found for most genes, and most discordant calls occurred at VAF < 1%. In longitudinal samples from progressing patients with endocrine resistance, we detected consistent alterations in sequential samples, most commonly in ESR1 and PIK3CA. Conclusion This study shows that both ultra-deep next-generation sequencing (NGS) technologies can detect genomic alternations even at low VAFs in plasma samples of mBC patients. The strong agreement of the technologies indicates sufficient reproducibility for clinical use as prognosic and predictive biomarker.

scholarly journals Uterine Fibroid in Breast Cancer Patients receiving Tamoxifen Therapy

2021 ◽  
pp. 59-62
Author(s):  
Rismawati Tambunan ◽  
Fahriatni ◽  
Hasanuddin
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Uterine Fibroid ◽  
Metastatic Breast ◽  
Selective Estrogen Receptor Modulators ◽  
Uterine Myoma ◽  
Tamoxifen Treatment ◽  
Breast Cancer Patients ◽  
Estrogen Receptor Modulators ◽  
Receptor Modulators

Abstract Objective: Selective estrogen receptor modulators (SERMs) such as tamoxifen play a role in increasing the risk of developing uterine Fibroid.Methods:  Case reportCase: Mrs. 47 years old, Para 6, presented with chief complaints of vaginal bleeding since a year ago. The patient was diagnosed with breast carcinoma 4 years ago and has had a right mastectomy followed by 6 cycles of chemotherapy which is  then continued with tamoxifen treatment for 4 years, USG examination revealed uterine myoma to which we performed bilateral salphingoophorectomy hysterectomy, with anatomic pathology results of a uterine Fibroid and chronic endometritis.Conclusion: Selective estrogen receptor modulators (SERMs) such as tamoxifen exhibit antagonistic reactions in breast tissue which makes it appropriate to be used in the treatment of breast cancer. However, they can also be potentially agonistic on estrogen receptors in the uterus, which can cause the growth of uterine Fibroid. Nevertheless, the benefits of adjuvant tamoxifen for breast cancer outweighs its potential for developing uterine Fibroid and endometrial carcinoma, because metastatic breast cancer will always be fatal, whereas uterine myoma and endometrial cancer caused by the effects of tamoxifen can be prevented by regular evaluation and total hysterectomy.Keywords: breast cancer,tamoxifen, uterine fibroid,   Abstrak Tujuan: Selektif estrogen reseptor modulator (SERMs) seperti tamoksifen berperan dalam meningkatkan risiko mengembangkan mioma uteri. Metode: Laporan KasusKasus: Ny 47 Thn Para 6, datang dengan keluhan perdarahan dari jalan lahir yang dirasakan ibu selama 1 tahun ini, pasien telah menderita kanker payudara 4 tahun yang lalu dan telah dilakukan mastektomi mammae dextra dilanjutkan kemoterapi 6 siklus kemudian dilanjutkan dengan pengobatan tamoksifen selama 4 tahun ini, dari pemeriksaan USG didapatkan adanya mioma uteri kemudian dilanjutkan dengan tindakan histerektomi salphingooforektomi bilateral, dengan hasil patologi anatomi suatu mioma uteri dan endometritis kronis.Kesimpulan: Selektif estrogen reseptor modulator (SERMs) seperti tamoksifen merupakan reaksi antagonis reseptor estrogen pada jaringan payudara yang digunakan dalam pengobatan kanker payudara, tetapi dapat berpotensi agonis pada reseptor estrogen pada uterus sehingga dapat menyebabkan pertumbuhan mioma uteri. Tetapi penggunaan tamoksifen  ajuvan untuk kanker payudara lebih bermanfaat dibandingkan dengan potensinya untuk mengembangkan mioma uteri dan karsinoma endometrium, karena  kanker payudara metastatik akan selalu berakibat fatal, sedangkan mioma uteri dan kanker endometrium yang ditimbulkan oleh efek tamoksifen dapat dicegah dengan evaluasi teratur dan dilakukan tindakan total histerektom.Kata kunci: kanker payudara, mioma uteri, tamoksifen

scholarly journals ARID1A Mutation in Metastatic Breast Cancer: A Potential Therapeutic Target

2021 ◽  
Vol 11 ◽  
Author(s):  
Xuan Cheng ◽  
Jian-Xiong Zhao ◽  
Feng Dong ◽  
Xu-Chen Cao
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Therapeutic Potential ◽  
Endocrine Resistance ◽  
Hdac Inhibitors ◽  
Treatment Strategies ◽  
Disease Free Survival ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Luminal A

Distant metastasis is the principal cause of mortality for breast cancer patients. Targeting specific mutations that have been acquired during the evolution process of advanced breast cancer is a potential means of enhancing the clinical efficacy of treatment strategies. In metastatic breast cancer, ARID1A is the most prevalent mutation of the SWI/SNF complex, which regulates DNA repair, recombination, and gene transcription. The low expression of ARID1A is associated with poor disease-free survival and overall survival of patients with luminal A or HER2-rich breast cancer. In addition, ARID1A plays a prominent role in maintaining luminal characteristics and has an advantage for identifying responses to treatment, including endocrine therapies, HDAC inhibitors and CDK4/6 inhibitors. The therapeutic vulnerabilities initiated by ARID1A alterations encourage us to explore new approaches to cope with ARID1A mutant-related drug resistance or metastasis. In this review, we describe the mutation profiles of ARID1A in metastatic breast cancer and the structure and function of ARID1A and the SWI/SNF complex as well as discuss the potential mechanisms of ARID1A-mediated endocrine resistance and therapeutic potential.

scholarly journals Molecular Mechanism of Secondary Endocrine Resistance in Luminal Breast Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Minhua Wu ◽  
Jinhua Ding ◽  
Limu Wen ◽  
Yuxin Zhou ◽  
Weizhu Wu
Keyword(s):  
Breast Cancer ◽  
Western Blot ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Endocrine Resistance ◽  
Akt Signaling ◽  
Luminal Breast Cancer ◽  
Akt Signaling Pathway ◽  
Secondary Resistance ◽  
Mcf 7

Objective. The molecular mechanism of secondary resistance in Luminal breast cancer was studied to provide new ideas for the treatment of breast cancer. Methods. The sensitivity of the downregulation of myeloid leukemia factor 1-interacting proteins (MLF1IP) to Tamoxifen (TAM) was tested by the Cell Counting Kit-8 (CCK-8). The apoptosis of MLF1IP-mediated resistance was analyzed by flow cytometry (FCM) with/without TAM. Western blot was used in detecting various kinds of apoptosis and the expression of the protein related to the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway to study the molecular mechanism of secondary endocrine resistance in Luminal breast cancer. Results. The downregulation of MLF1IP could significantly increase the drug sensitivity of Michigan Cancer Foundation-7 (MCF-7) cells and also inhibit the proliferation of MCF-7 cells under the stimulation of drugs. Western blot results showed that the expression of Bcl-2-associated X (BAX), Caspase3, Caspase7, and Caspase9 proteins increased when MLF1IP was downregulated. The results of the PI3K/AKT signaling pathway revealed that the phosphatase and tensin homolog deleted on chromosome ten (PTEN) protein expression of MCF7-shRNA was higher than that of MCF7-NC cells, while the expression of p-AKT was lower than that of MCF7-NC cells. Conclusions. (1) MLF1IP-related apoptosis resistance plays an essential role in MLF1IP-mediated secondary resistance of breast cancer cells. (2) MLF1IP promotes AKT phosphorylation by inhibiting the PTEN expression, thus activating the PI3K/AKT signaling pathway and causing the secondary resistance of Luminal breast cancer. (3) MLF1IP can be used as a factor to predict the endocrine resistance of Luminal breast cancer.

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