الفهرس 
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Abstract
Breast cancer is the most common cancer and also the leading cause of cancer mortality in women worldwide. Although many drugs and therapeutic regimens have been developed for the treatment of breast cancer, there is no cure for patients with systemic metastatic breast cancer. Diagnosis of breast cancer during its early stages correlates with increased overall survival rate. Therefore, females with high risk of developing breast cancer are encouraged to undergo mammograpghy on an annual basis. However, tumors could evade detection by conventional physical examinations during their early stages.
Hypoxia is common in various types of solid cancers and is associated with a more aggressive phenotype. Stabilization of the α-subunit of the hypoxia-inducible transcription factor 1 (HIF-1α) is a critical step in the adaptation of tumor cells to hypoxia.
Angiogenesis is an important mediator of tumor progression. Sustained expansion of tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and metabolites.
CAIX is a hypoxia-induced, cell surface enzyme involved in pH regulation of hypoxic solid tumors. CAIX hydrated carbon dioxide to produce bicarbonate and protons. The protons accumulate in the extracellular space and contribute to acidification of the tumor microenvironment (TME), while the bicarbonate via bicarbonate transporters is retained inside the cell facilitating the titration of intracellular pH.CAIX plays a role in tumor growth, survival, invasion and metastasis.
CD34 is a transmembranephosphoglycoprotein, first identified in 1984 on hematopoietic stem and progenitor cells. It has a molecular weight of approximately 115 kDa since CD34 is an antigen present in hematopoietic progenitor cells and endothelial cells,it is closely associated with the process of angiogenesis.
The protocadherin 17 gene, encoding the protocadherin 17 protein has been identified as a tumor suppressor gene and is frequently downregulated in several cancers includind gastric, nasopharyngeal carcinoma and renal carcinoma.
The present study aimed to evaluate the angiogenic CD34 and hypoxia Carbonic Anhydrase IX markersand their relation to the new blood vessel marker Protocadherin 17 gene expression in female patients with breast cancer.
Individuals submitted inthis study were divided into 2 main groups:
group I: 50 females breast cancer patients.
group II: 40 healthy females matched in age and menopausal status with patients group served as control group.
5 ml of venous blood were withdrawn from all breast cancer patients (before surgery) and from the healthy control group. This blood sample was divided into two aliquots:
- The first (3 ml) was allowed to clot thoroughly for 30 minutes then centrifuged at 1000 xg for 15 minutes for separating serum. Serum was stored at -80ºC until used for assaying CAIX by ELISA.
- The second part (2ml) was pipetted into a tube containing EDTA for the evaluation of CD34 marker by flow cytometry.
- Also tumor tissue and adjacent normal breast tissue were collected from female patients with breast cancer and were frozen at -80˚C until being used forassaying protocadherin 17 gene expression by Real time PCR.
Our results showed that:
1. The mean value for serum CAIX in breast cancer patients was statistically significantly higher than that in control subjects.
2. According to the result of the present study, the mean value for the percent of CD34+ cells in breast cancer patients was statistically significantly higher than that in control subjects.
3. The mean value for PCDH17 gene expression in breast cancer tissues was significantly lower than that in normal adjacent breast tissues.
4. Serum CAIX was significantly positively correlated with clinical stage of patients, tumor size and axillary lymph node invasion while there was insignificant correlation with PCDH17 gene expression, histological grade, ER status, PR status, Her-2/neu expression and vascular invasion.
5. Regarding CD34, it was positively correlated with serum CAIX, histological grade of the tumor and vascular invasion while there was insignificant correlation with PCDH17gene expression, clinical stage of patients, tumor size, axillary lymph node invasion, ER status, PR status andHer-2/neu expression
6. Our results showed that PCDH17 gene expression was insignificantly correlated with either CD34 or CAIX as well as other clinicopathological parameters.
7. These results demonstrated that in breast cancer patients the sensitivity of serum CAIX was higher than PCDH17 and superior to CD34 for diagnosis of breast cancer patients.
from the present study we can conclude that:
1- Serum CAIX and CD34+cells were significantly higher in breast cancer patients compared to controls and both were significantly positively correlated. This may emphasize the role of hypoxia in stimulating the production of angiogenic markers such as CD34.
2- PCDH17 gene was downregulated in breast cancer tissues compared to normal breast tissues.
3- Our study can be considered to be the first one to estimate CD34, serum CAIX and PCDH17 gene expression together in breast cancer patients.
4- Serum CAIX may play a valuable role in diagnosis of breast cancer with high sensitivity and specificity.
Recommendations
1- Anti-angiogenic therapy may be beneficial in those breast cancer patients to prevent further angiogenesis and to suppress invasion and metastasis.
2- Further large-scale studies are warranted to investigate the new opportunity for CAIX targeted therapy.
3- Serum CAIX and CD34+ cells may work as new diagnostic tools in the screening and diagnosis of breast cancer.
4- Future studies of mechanisms regulating PCDH17 down regulation are requiredin order to explain the mechanism for its downregulation in breast cancer.
5- Further follow up study is required to determine the prognostic significance of the studied parameters.