Evaluation of the role of serum tissue inhibitor of matrix metalloproteinase 1 (timp-1)‎ in vascular endothelial growth factor (vegf)‎ induction and their role in prognosis of breast cancer patients

الملخص EN

Background : High levels of TIMP-1 have been implicated in progression of several human cancers, including breast cancer.

TIMP-1 expression profile could be the result of its action as a multifunctional molecule.

Proposed functions include growth promotion and anti-apoptotic effects as well as both anti- and pro-antigenic functions.

TIMP-1 has been implicated in the process of angiogenesis most probably by directly stimulating the expression of VEGF that promotes angiogenesis of the tumor.

Aim : The aim of this study is to measure the levels of TIMP-1 and VEGF-A in serum of breast cancer patients to elucidate the possible correlation between the two.

Also to assess the prognostic significance of each of them compared to the standard marker of breast cancer, CA 15.3.

Methods : The study included 45 females divided into 2 groups; Group I included 30 females recently diagnosed with breast cancer, and Group II included 15 normal healthy females of matched age to the first group.

Three blood samples were taken from each patient of Group I before surgery, 2 weeks after surgery and after 6 cycles of treatment.

Also, a blood sample was taken from each of Group II subjects.

All sera were kept frozen at -80°C until used.

Patients were followed up for 2 years after treatment with adjuvant chemotherapy.

TIMP-1, VEGF-A and CA 15.3 were assayed in all serum samples using commercially available ELISA kits.

Patients of group I were subjected to Modified Radical Mastectomy.

Results : Both TIMP-1 and VEGF-A levels in the malignant group, before surgery, were significantly higher than their corresponding levels in the control group, and they remained unchanged after surgery and after treatment.

While CA 15.3 level of the malignant group before and after surgery was not statistically significantly different from the control group, but after treatment it was statistically significantly higher than the control group.

The Receiver Operator Characteristics (ROC) curve showed that both TIMP-1 and VEGF-A were convenient diagnostic markers (Area Under Curve (AUC) = 91.4% and 97.8%, respectively), but not CA 15.3.

The optimum cutoff point for VEGF was 50.0 pg / ml, with a corresponding sensitivity of 94.0% and specificity of 100%.

While the optimum cutoff point for TIMP-1 was 665 ng / ml, with a corresponding sensitivity of 86.7% and specificity of 83.3%.

As prognostic marker, Disease Free Survival (DFS) curves showed that both of VEGF-A and TIMP-1were statistically significant (p=0.047 and 0.045, respectively), indicating a significant difference in survival between VEGF-A positive and VEGF-A negative, and between TIMP-1 positive and TIMP-1 negative breast cancer patients.

However, there was no statistically significant difference in survival between CA 15.3 positive and CA 15.3 negative breast cancer patients (p=0.514).

A highly significant correlation was found to exist between serum levels of TIMP-1 and VEGF-A in all females enrolled in the study (r=0.568 and p=0.000).

Such correlation may support the hypothesis that TIMP-1 induced VEGF-A might be an important factor in vascularization of breast cancers and subsequent development of metastasis.

Conclusions : In conclusion, both preoperative serum TIMP-1 and serum VEGF-A were proven to be of diagnostic as well as prognostic significance in females with primary breast cancer, but not preoperative serum CA-15.3.

However, serum levels of CA 15.3 after treatment were indicative of metastasis.

TIMP-1 and VEGF-A were highly correlated to each other, which might support the hypothesis that TIMP-1 induces VEGF-A in breast cancer patients.