Increased YAP1 expression is significantly associated with breast cancer progression, metastasis and poor survival.

YAP1 plays a key role as a transcriptional coactivator in the Hippo pathway. Based on conflicting reports regarding YAP1 function in cancer, this study discerned its role in breast carcinogenesis. First, a systematic review of salient breast cancer studies targeting YAP1 dysregulation was performed. Additionally, freshly excised tumor specimens of approximately 200 breast cancer patients were processed for quantification of YAP1 expression at mRNA and protein levels using quantitative PCR and immunohistochemistry, respectively. YAP1 expression was nine folds higher in tumors versus controls and significantly associated with metastasis (p < 0.05) and poor survival in Pakistani breast cancer patients. These findings establish the role of YAP1 overexpression in tumorigenesis and metastasis. Hence, YAP1 inhibition may be considered a possible therapeutic strategy.

Lay abstract Breast cancer incidence and prevalence are rapidly increasing across the globe, especially in countries with poor screening interventions, culminating in delayed diagnosis and greater mortality. Furthermore, for the adequate treatment of breast cancer, treatment plans must be individualized. In this context, the present study was devised to add to the existing pool of information with regard to breast cancer. In addition, the authors wanted to see whether YAP1 (the gene of interest) significantly contributes to breast cancer progression and its spread to distant areas of the body. Also, the authors aimed to study the effect of this gene on survival in breast cancer patients. Knowing the role of YAP1 in breast cancer, it is imperative to make use of this gene in devising treatment strategies for the proper management of breast cancer patients.

Expression analysis of human epidermal growth factor receptor type 2 transcripts in breast cancer cohort and its association with clinical features.

AIM OF STUDY: Increased expression of human epidermal growth factor receptor type 2 (HER2) is significantly associated with poor prognosis in breast cancer patients. However, data on HER2 at transcript levels in Pakistani mammary tumor affected females is still limited. In the current study, HER2 transcripts were explored in breast cancer cohort and correlated with various clinical parameters. MATERIALS AND METHODS: Freshly excised tumors along with adjacent normal background tissues of 94 patients were collected at the time of surgery and immediately stored in RNAlater ® solution. Clinical data for these samples (disease stage, grade, age, and menopausal status) was also retrieved after a subsequent follow-up. Isolation of RNA and cDNA synthesis was done using an already established protocol. HER2 expression was evaluated using the quantitative real-time polymerase chain reaction (qRT-PCR) technique while ß-actin was used as an internal control. RESULTS: In the given cohort, 31 (33%) patients were found positive for HER2. These tumors showed a pronounced increase in HER2 as compared to controls (P = 0.0004). Interestingly, the significant relevance of high HER2 mRNA among moderately differentiated tumor tissues in comparison to controls was also observed (P = 0.02). A significant association of HER2 levels with premenopausal status was also reported. CONCLUSION: Based on these findings, early screening of HER2 using qRT-PCR should be incorporated for breast cancer patients of Pakistani population diagnosis.

Role of HER-2 Ile655Val Polymorphism as Universal Cancer Susceptibility Marker among Different Cancers.

BACKGROUND: Genetic and expression anomaly of HER-2 have been frequently observed in different cancers. However, an overall association of HER-2 polymorphism (Ile655Val) with available cancer studies has not yet been explored. In the present study, a probable correlation of HER-2 Ile655Val polymorphism with 6 major types of cancers including breast, lung, gastric, ovarian, thyroid and uterine has been collectively assessed. METHODOLOGY: Extensive data mining was performed using online available medical research databanks including Pubmed, Ovid, Medline and Embase. Research articles were retrieved based on common keywords "HER-2, polymorphism, (SNP) and cancer (including breast, gastric, lung, ovarian, thyroid and uterine). A database was maintained and updated for case control studies of HER-2 genotype Ile655Val (rs1136201) information until February 2015. Based on selection criteria, a total of 41 studies containing 37,111 subjects (17845 patients, 19266 controls) were selected for thorough insight about HER-2. RESULTS: A significant risk association of HER-2 Ile655Val polymorphism was observed in different types of cancer using various genetic models (co-dominant heterogeneous Ile/Val vs Ile/Ile; OR=1.1, 95% CI = 1.01-1.16, P = 0.01 and dominant; OR = 1.12, 95% CI = 1.03-1.20, P = 0.0003). Interestingly, a strong correlation of Ile655Val heterogeneity was seen in the stratified subgroup of different population including African-American (co-dominant homogenous Val/Val vs Ile/Ile; OR = 8.7, 95% CI = 2.5-30.4, P = 0.0001, dominant; OR = 1.3, 95% CI = 1.03-1.7, P = 0.003; recessive; OR = 8.3, 95% CI = 2.4-28, P = 0.0002), Caucasians (co-dominant heterogeneous Ile/Val vs Ile/Ile; OR = 1.1, 95% CI = 1.0 - 1.2, P = 0.03, dominant; OR = 1.12, 95% CI = 1.0-1.2, P = 0.01). However, in Asian ethnic group, Ile655Val polymorphism lacked a significant association with cancer. This may be attributed to limited studies explored so far. CONCLUSION: In summary, the current study reveals a significant association between cancer susceptibility and the HER-2 Ile655Val polymorphism in all genetic models.

Review-Therapeutic implications of Nigella sativa against cancer metastasis.

Nigella sativa (N. sativa), remedial usage against different diseases associated with skeleton, cardiovascular, digestive and urinary systems has a long-standing history. At present, efforts are underway to study its effects against various cancers at both the cellular and molecular levels. In this review, the role of active constituents like thymoquinone (TQ) on different types of cancer has been explored. TQ putative involvement in metastasis has been assessed by elucidating its effects on cell proliferation, adhesion, invasion and angiogenesis. Up regulation of caspase 3, Smac and down regulation of p-AKT, p65, XIAP, Bcl-2, COX-2 is also influenced by N. sativa. These findings prove a significant positive correlation between TQ concentrations and induction of apoptosis, decrease in motility and a reduction in invasion and angiogenesis in cancerous cells. However, there are still quite a few unaddressed domains, which need to be understood. One of these may include target specificity of N. sativa against cancerous tissues, mode of administration, dosage and downstream regulators in mediating these effects. In reference to earlier findings and low cost availability, N. sativa may, also, be suggested as either a suitable sole remedy for cancer or as a complementary to ongoing conventional therapy based extensive and rigorous in vivo optimization and validation.

Influence of microvesicles in breast cancer metastasis and their therapeutic implications.

 Microvesicles are membranous sac structures released from cell surfaces of many eukaryotic cells. Their presence in the blood and urine also signify their potential use as biomarkers for early detection and diagnosis of different diseases. At present, synthesis and release of these vesicles from mammary tumor cells and their role in disease progression requires further research. In this report, correlation of microvesicles along with breast cancer metastasis has been explored. Metastasis is a process of a non-randomized set of events, which begins with a loss of cancer cell adhesion at the primary tumor site. Later on, these cells invade the surrounding tissue and enter into circulation. After compromising host immune response, these cells extravasate and localized at the suitable distant site for a secondary growth. Involvement of microvesicles in modulating this process has also been observed. Microvesicles released from primary cancer cells may carry mRNA, miRNAs, DNA and various proteins. These vesicles may also influence multi drug resistance as observed in breast and leukemia cancer cell lines. A thorough understanding of microvesicles synthesis and their potential implication in metastasis would facilitate the design of novel therapeutic approach for breast cancer.