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Abstract Breast tumors are well known to be composed of phenotypically diverse groups of cells; however, it is unclear which of these cell types contribute to tumor development. In contrast to the hypothesis that all cell populations have the capacity to become tumorigenic through accumulation of mutations, another hypothesis limits this ability to an elite group of cells that share classic features of stem cells. There is increasing evidence suggests that the existence of a small population of specialized cancer cells that display stem-cell properties, commonly referred to as cancer stem cells (CSCs) or cancer initiating cells. CSCs are characterized by their ability to self-renew, differentiate into various lineages, and reconstitute the cellular hierarchy of the tumor from which they are derived in serial xenotransplant assays. These cells are highly resistant to chemo- and radiotherapy and are believed to be responsible for tumor recurrence following therapeutic intervention. Aim of the work: In the present study, we attempted to investigate the role of cancer stem cell marker CD44 and its ligand HA in breast cancer patients and their impact on apoptosis stimulating protein P53 and VEGF. Subjects and methods: Fourty female patients who were newly diagnosed with BC were enrolled into the study as patient groups. Fourty women with normal mammography findings and no previous history of any kind of cancer with matched age and menopausal status served as control group. Venous blood sample was collected concurrently from each breast cancer patient (Before surgery) and from the control group. All blood samples we obtained at fasting early in the morning and the serum was immediately separated by centrifugation and stored at -70° until use. Serum hyaluronan, p53 and VEGF levels were measured by enzyme linked Immunosorbent assay. Tumor tissue was collected from each patient with breast cancer and tissue expression of CD44 was evaluated by immunohistochemical staining for malignant group. Patients were followed up clinically, radiologically and by laboratory testing for 24 months to assess the prognostic value of the markers. Results and Discussion: According to the results of the present study, the expression of CD44 protein was examined in BC tissues of 40 BC patients and 40 adjacent normal control tissues. The result offered evidence that CD44 protein was remarkably expressed in 70% of breast tumor tissues in comparison with normal counterparts at protein level indicating that CD44 might participate in the tumorigenesis of breast cancer. Additionally, our results suggest a positive significant correlation between histological grade and the CD44 protein expression levels. This would indicate these patients with high CD+ 44 protein abundance might have poor prognosis, because high grade Summary and Conclusions 82 tumor tends to be more aggressive and tends toward early recurrence. Moreover, CD44 protein abundance tended to be positively significantly correlated with clinical stage indicating that this molecule may be considered as a biological tumor marker for estimating the occurrence and progression of BC regardless of treatment. It was demonstrated that CD44 tended to be negatively correlated with ER, PR and truly associated with HER2 which are already tested as poor prognostic markers. Therefore CD44 might play an important role in breast tumor genesis and malignant transformation. According to a survival analysis the results showed that patient whose tumors coexpressed CD+ 44 were prone to have shorter disease-free survival time than CD- 44 tumors. The log rank value was (4.841). Our data indicated that CD+ 44 might be used as a biomarker to predict patient who are at increased risk for progression of cancer metastasis or relapse. The present study revealed that serum HA levels are highly elevated in breast cancer patients in comparison to control group with significant elevation in patients with positive CD44 protein expression than CD44 negative patients. This result is expected since HA is synthesized from carcinoma cells and stromal cells which are also a rich source of this biopolymer and may point to the role of CD44 in up-regulating HA. Furthermore, it was noticed that serum HA was positively correlated with histological grade and vascular invasion and negatively correlated with ER and PR expression. These results clearly showed the role of HA in carcinogenesis and progression of breast cancer. In this study the relationship between serum HA and prognosis was analyzed by evaluating DFS in total 40 female patients. The analyses of DFS showed that higher level of this parameter is significantly associated with poor prognosis in patients with breast cancer. In the current study, we found a close relationship between VEGF and CD44. Patients with positive CD44 protein expression had a mean serum VEGF that was significantly higher than either breast cancer patients with negative CD44 expression or healthy controls. Thus, we draw a conclusion that CD+ 44 served as an up-regulator of VEGF to function in the progression of BC. Therefore the results suggest that CD+ 44 protein abundance may be critical for driving angiogenesis by secreting VEGF. Our study revealed that in all breast cancer patients p53 levels were significantly lower than in control group. Moreover, decreased p53 serum levels are associated with elevated CD44 protein expression in breast cancer patients. These findings lead us to suggest that aberrant CD44 protein expression is advantageous for the growth, survival and dissemination of tumor cells. |