Abstract
ABSTRACT
Breast cancer remains a leading cause of cancer-related mortality among women worldwide and continues to pose substantial challenges for early detection and prognostic stratification. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous regulators of matrix metalloproteinase (MMP) activity and play an important role in maintaining extracellular matrix (ECM) homeostasis. Among this family, TIMP-3 is distinguished by its strong affinity for the ECM and its involvement in biological processes relevant to tumor progression, including angiogenesis, cellular invasion, and metastatic spread. Despite growing interest in TIMP-3 as a potential biomarker, its circulating levels and genetic regulation in breast cancer remain incompletely characterized, particularly across different populations. This case-control study included 50 breast cancer patients and 30 age-matched healthy controls between August 2024 and March 2025 at Nanakaly Hospital in Erbil.
This study aimed to examine the relationship between plasma TIMP-3 concentrations, TIMP3 promoter polymorphisms, and breast cancer status (susceptibility and clinicopathological characteristics) by comparing patients with age-matched healthy controls from Erbil City. Plasma TIMP-3 levels were quantified using enzyme-linked immunosorbent assay (ELISA), while promoter polymorphisms were identified through DNA sequencing. Genotype and allele frequencies were compared between groups, and circulating TIMP-3 levels were evaluated in relation to clinical and pathological characteristics.
Overall, no statistically significant difference in circulating TIMP-3 levels was observed between breast cancer patients and healthy controls. However, subgroup analyses indicated lower TIMP-3 concentrations among patients receiving (5-8) chemotherapy regimens and those diagnosed with grade II tumors relative to controls. Genetic analysis identified several previously reported TIMP3 promoter variants, including rs9619311, rs1390587086, rs968107761, and rs1021986044, as well as three novel sequence variants. A significant association was detected between the rs1390587086 G>C polymorphism and breast cancer status, with the G allele and GG genotype more frequently observed among patients. An additional allelic association was noted for the novel variant 32800530 G>A. Notably, none of the analyzed promoter variants showed a significant relationship with circulating TIMP-3 concentrations.
In conclusion, the findings suggest that neither circulating TIMP-3 levels nor the examined TIMP3 promoter polymorphisms constitute strong independent indicators of breast cancer susceptibility in this population. The observed genetic associations, in the absence of corresponding changes in plasma protein levels, underscore the complexity of TIMP3 regulation and point to the need for further studies incorporating tissue-based analyses, functional assays, and complementary molecular markers to clarify the biological relevance of TIMP3 variation in breast cancer.
