Relationships between hypoxia markers and the leptin system, estrogen receptors in human primary and metastatic breast cancer: effects of preoperative chemotherapy

Background: Tumor hypoxia is marked by enhanced expression of hypoxia-inducible factor-alpha (HIF-1 alpha) and glucose transporter-1 (Glut-1). Hypoxic conditions have also been associated with overexpression of angiogenic factors, such as leptin. The aim of our study was to analyze the relationships between hypoxia markers HIF-1 alpha, Glut-1, leptin, leptin receptor (ObR) and other breast cancer biomarkers in primary and metastatic breast cancer in patients treated or untreated with preoperative chemotherapy. Methods: The expression of different biomarkers was examined by immunohistochemistry in 116 primary breast cancers and 65 lymph node metastases. Forty five of these samples were obtained form patients who received preoperative chemotherapy and 71 from untreated patients. Results: In primary tumors without preoperative chemotherapy, HIF-1 alpha and Glut-1 were positively correlated (p = 0.02, r = 0.437). HIF-1 alpha in primary and metastatic tumors without preoperative therapy positively correlated with leptin (p < 0.0001, r = 0.532; p = 0.013, r = 0.533, respectively) and ObR (p = 0.002, r = 0.319; p = 0.083, r = 0.387, respectively). Hypoxia markers HIF-1 alpha and Glut-1 were negatively associated with estrogen receptor alpha (ER alpha) and positively correlated with estrogen receptor beta (ER beta). In this group of tumors, a positive correlation between Glut-1 and proliferation marker Ki-67 (p = 0.017, r = 0.433) was noted. The associations between HIF-1 alpha and Glut-1, HIF-1 alpha and leptin, HIF-1 alpha and ER alpha as well as Glut-1 and ER beta were lost following preoperative chemotherapy. Conclusions: Intratumoral hypoxia in breast cancer is marked by coordinated expression of such markers as HIF-1 alpha, Glut-1, leptin and ObR. The relationships among these proteins can be altered by preoperative chemotherapy.