Triple Negative Breast Cancer: Molecular Classification, Prognostic Markers and Targeted Therapies

Jafarzadeh, Narges; Ashraf, Hami; Khoshroo, Fahimeh; Shamloo, Alireza Sepehri; Bidouei, F; Ghaffarzadehgan, Kamran

doi:10.5812/rijm.3(2)2015.24992

Cited by 3 publications

(1 citation statement)

References 67 publications

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“…Apart from the mentioned limitations, there is little information on radiological diagnosis of breast cancer at early ages ( 12 ). On the other hand, there is no definite correlation among mammographic imaging findings with the breast cancer histologic type and prognostic markers ( 13 ). The HER2 oncogene as a prognostic marker encodes transmembrane glycoprotein with tyrosine kinase activity, and its overexpression can be seen and acts as a proto-oncogene ( 14 , 15 ).…”

Section: Introductionmentioning

confidence: 99%

Relationship among mammographic findings with histopathologic type of breast cancer and human epidermal growth factor receptor 2 (HER2) in young women

2017

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IntroductionRadiological measures to diagnose breast cancer, including mammographic and ultrasound assessments in young women, are associated with restrictions affecting the use of this tool. No adequate information is available on mammography view in young people with breast cancer and its relationship with pathologic type and epidermal growth factor receptor 2 (HER2) as a prognostic marker, especially in the Iranian race. This study was conducted to examine the relationship between mammographic findings of young women with breast cancer with diagnosed histopathologic type and HER2 marker status.MethodsThis retrospective cross-sectional study was carried out on women with breast cancer referred to Omid Hospital in Mashhad, Iran. Inclusion criteria were age less than 45 years and definitive diagnosis of breast cancer documented in the patient record. Information on mammographic findings such as mass, asymmetry, microcalcification, tissue distortion, nipple retraction, and skin thickening was collected from patient medical records. In addition, the type of pathology diagnosed based on biopsy samples and HER2 examination results were collected. The chi-square test and SPSS software were used to analyze the relationship among qualitative variables.ResultsThis study was performed on 153 patients with a mean age of 39.3±2.5 years (minimum 20 years and maximum 45 years). The mammographic finding was reported normal in 41 patients (26.7%). The evidence of malignant mass was observed in 48 patients (31.3%). The microcalcification was found in 31 patients (20.3%). The retraction or thickening of breast tissue was seen in 39 patients (25.5%). The distortion of breast stroma was found in 41 patients (26.8%). The HER2 marker in 76 patients (49.7%) was positive in study subjects. There was no statistically significant association between mammographic findings and pathologic type. Among the mammographic findings, only the presence of microcalcification had significant association with HER2 results (p=0.008).ConclusionIt seems that a significant relationship could not be found between mammographic features in patients with breast cancer and type of pathology diagnosed. However, the presence of calcification in mammography is associated with positive HER2.

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Section: Introductionmentioning

confidence: 99%

Relationship among mammographic findings with histopathologic type of breast cancer and human epidermal growth factor receptor 2 (HER2) in young women

2017

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Emergence of a Promising Lead Compound in the Treatment of Triple Negative Breast Cancer: An Insight into Conformational Features and Ligand Binding Landscape of c-Src Protein with UM-164

Ndagi

Mhlongo

Soliman

2017

Appl Biochem Biotechnol

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UM-164, a potent Src/p38 inhibitor, is a promising lead compound for developing the first targeted therapeutic strategy against triple-negative breast cancer (TNBC). However, lack of understanding of conformational features of UM-164 in complex with Src serves a challenge in the rational design of novel Src dual inhibitors. Herein, we provide an in-depth insight into conformational features of Src-UM-164 using different computational approaches. This involved molecular dynamics (MD) simulation, principal component analysis (PCA), thermodynamics calculations, dynamic cross-correlation (DCCM) analysis, and hydrogen bond formation. Findings from this study revealed that (1) the binding of UM-164 to Src induces a more stable and compact conformation; (2) the binding of UM-164 results in increased correlation among the active site residue; (3) the presence of multiple phenyl rings and fluorinated phenyl group in UM-164 contributes to the steric effect; (4) a relatively high-binding free energy estimated for the Src-UM-164 system is affirmative of its experimental potency; (5) hydrophobic packing contributes significantly to the drug binding in Src-UM-164; and (6) observed increase in H-bond distance of interacting residue atoms and Dasatinib compared to UM-164. Findings from this study can serve as a baseline in the design of novel Src inhibitors with dual inhibitory properties.

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The impact of Thr91 mutation on c-Src resistance to UM-164: molecular dynamics study revealed a new opportunity for drug design

2017

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The emergence of a drug resistant non-receptor tyrosine kinase (c-Src) in triple-negative breast cancer (TNBC) remains a prime concern in relation to the burden of TNBC among people living with breast cancer and drug development. Thr91 mutation was found to induce a complete loss of protein conformation required for drug fitness. Herein, we provide the first account of the molecular impact of the Thr91 mutation on c-Src resistance to experimental drug UM-164 using various computational approaches, namely molecular dynamics simulation, principal component analysis (PCA), dynamic cross-correlation matrices (DCCM) analysis, hydrogen bond occupancy, thermodynamics calculation, ligand-residue interaction and residue interaction networks (RINs). Findings from this study revealed that Thr91 mutation leads to a steric conflict between UM-164 and the side chain of methionine (Met91); this mutation distorts the UM-164 optimum orientation on the conformational space of mutant c-Src compared to the wild-type; decreases hydrogen bond formation between the residues in the mutant protein structure; decreases the UM-164 binding energy in the mutant by -13.416 kcal mol; reduces the residue correlation in the mutant protein structure; induces a change in the overall protein structure conformation from an inactive to active conformation; and distorts the ligand atomic interaction network and the residue interaction network. This report provides important insights that will assist in the further design of novel dual kinase inhibitors to minimise the chances of drug resistance in triple negative breast cancer.

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Triple Negative Breast Cancer: Molecular Classification, Prognostic Markers and Targeted Therapies

Cited by 3 publications

References 67 publications

Relationship among mammographic findings with histopathologic type of breast cancer and human epidermal growth factor receptor 2 (HER2) in young women

Relationship among mammographic findings with histopathologic type of breast cancer and human epidermal growth factor receptor 2 (HER2) in young women

Emergence of a Promising Lead Compound in the Treatment of Triple Negative Breast Cancer: An Insight into Conformational Features and Ligand Binding Landscape of c-Src Protein with UM-164

The impact of Thr91 mutation on c-Src resistance to UM-164: molecular dynamics study revealed a new opportunity for drug design

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