Breast cancer is the most common tumor in women and the second most common cause of cancer-related deaths. According to cancer data published in 2021, approximately 2,260,000 women were diagnosed with breast cancer, and 684,996 women died due to breast cancer [1,2]. Over the past 20 years, breast cancer has been recognized as a family of diseases with distinct pathological, molecular, and clinical characteristics. Various classification systems have been proposed, affecting prognosis and treatment. It has been categorized into estrogen/progesterone receptor-positive (luminal), Her2 receptor-positive, and triple-negative breast carcinoma (TNBC), where all three receptors are negative [3]. TNBCs account for approximately 15% of all breast cancer cases. They are more common in women under 40 years of age and have shorter survival rates compared to other types of breast cancer. Approximately 40% of women with TNBC die within the first five years after diagnosis. Distant metastasis is observed in around 46% of TNBC patients with a mean survival time of 13,3 monts after metastasis [1, 3].
Since Warburg's study in 1927 revealed the so-called Warburg effect, which is characterized by irregular glucose uptake and disruption of glycolytic metabolism in cancer cells, irregular energy metabolism has become known as an important part of the pathogenesis behind uncontrolled growth in cancer cells [4].
Hypoxic areas are commonly found in more than half of breast tumors due to high metabolic proliferative rates and abnormal vascularization. In healthy breasts, the average oxygen pressure (pO2) is 65 mmHg, whereas in breast tumors, it is reduced to 10 mmHg. Tumor areas exhibit acidic pH (< pH6.5) [5]. Hypoxia poses a life-threatening condition for all aerobic organisms, and they develop various adaptation mechanisms to survive in such conditions [6]. The rapid proliferation of cancer cells increases the demand for oxygen, but the vessels supplying oxygen-carrying blood cannot keep up with this speed. Consequently, hypoxia occurs in rapidly growing tumor tissues, and tumor cells develop adaptive responses to cope with this stress [7]. Hypoxia can be moderate or severe, acute or chronic, and intermittent or persistent, leading to various cellular responses that promote aggressive tumor phenotypes [8]. At the molecular level, these changes are primarily determined through the remodeling of hypoxia-inducible factor (HIF)-mediated transcriptional profiles [9]. HIF targets genes that encode angiogenesis mediators such as vascular endothelial growth factor (VEGF) and VEGF receptors, as well as enzymes involved in the glycolytic pathway such as hexokinase 2, lactate dehydrogenase, and glucose transporters (GLUT-1 and GLUT-3). Additionally, it affects erythropoiesis, vascular remodeling, cell proliferation and viability, cell adhesion, cell-matrix metabolism, and pH regulation [8].
Due to the development of hypoxia and increased energy demand, glycolysis is enhanced, leading to the production of excess acidic metabolic end products such as lactic acid, protons, and carbon dioxide. This activation triggers pH regulatory mechanisms. Intracellular acidosis is usually eliminated by CO2 diffusion, removal of lactate and protons from the cell, and intake of bicarbonate ions. However, since tumor vessels cannot effectively remove acidic metabolic waste, pericellular acidosis often persists in the tumor microenvironment [10].
Carbonic anhydrase IX (CA IX) is a tumor-associated cell surface glycoprotein that aids in adaptation to acidosis induced by hypoxia and plays a role in cancer progression. The active site of the CA IX enzyme in the catalytic domain is positioned towards the extracellular space, contributing to pH regulation across the plasma membrane by facilitating CO2 hydration. This, in turn, enhances CO2 diffusion and proton mobility in the tumor tissue. Simultaneously, CA IX exacerbates extracellular acidosis, which can activate proteases to degrade the extracellular matrix, promote epithelial-mesenchymal transition and invasion, reprogram metabolism, affect cell adhesion, and stimulate inflammation and angiogenesis. CA IX is more abundant in tumor tissues compared to normal tissues [11, 12].
Many tumor studies have reported CA IX overexpression as a poor prognostic marker. Previous clinical trials on invasive breast cancer have also demonstrated that CA IX is associated with poor outcomes, suggesting its relationship with an aggressive phenotype. CA IX overexpression has also been associated with low disease-free survival time in invasive breast cancer. However, there is insufficient information regarding its role in TNBC [13].
TNBCs have poor prognoses and are resistant to chemo-radiotherapy, making them a focal point of cancer research. In this study, we investigated the relationship between CA IX expression and prognostic factors of TNBC, as well as its contribution to treatment. The aim was to identify the causes of poor prognosis and make recommendations for exploring new treatments.