Expression of Hypoxia-inducible factor 1-alpha and Vascular endothelial growth factor-C in locally advanced breast cancer patients (original) (raw)
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Cancer, 2003
BACKGROUND. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis to survive cellular hypoxia. Increased levels of HIF-1␣, the O 2 -regulated subunit of HIF-1, were noted during breast carcinogenesis. In this study, the prognostic value of HIF-1␣ expression and its correlation with various clinicopathologic variables in patients with invasive breast carcinoma were investigated.
Clinical Cancer Research, 2006
Purpose: To investigate the relationship of hypoxia-inducible factor-1a (HIF-1a) tumor expression in predicting the response to epirubicin and disease-free survival (DFS) in patients with breast cancer enrolled in a single institution trial of primary anthracycline and tamoxifen therapy. Experimental Design: The expression of HIF-1a was assessed by immunohistochemistry in 187 patients with T 2-4 N 0-1 breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin + tamoxifen as primary systemic treatment. All patients postoperatively received four cycles of the four weekly i.v. CMF regimen (cyclophosphamide, methotrexate, and 5-fluorouracil). Patients with estrogen receptor (ER)-positive primary tumors also underwent 5 years of treatment with adjuvant tamoxifen. Carbonic anhydrase IX (CAIX) was also scored as a marker of HIF activity. Results: Overall response to therapy progressively decreased with increasing tumor HIF-1a (P < 0.05), and HIF-1awas an independent predictor of response (P < 0.048). HIF-1aexpression was also associated with a significantly shorter DFS (P < 0.02) in all patients and in ER-positive but not in ER-negative patients. Furthermore, CAIX positivity conferred a significantly shorter DFS (P = 0.02) compared with CAIX-negative tumors in patients with HIF-1a-negative tumors. Conclusions: HIF-1a expression in patients with breast cancer is a marker of poor therapy response and outcome, especially in ER-positive patients. The combination of two hypoxia markers has greater utility than assessing just one, and patients with hypoxia markers in their tumors may be suitable for administration of drugs that reduce HIF-1a expression and increase oxygen delivery to the tumor bed before starting neoadjuvant therapies.
Journal of International Dental and Medical Research, 2019
Advanced breast cancer may aggressively progress under hypoxic conditions, leading to therapy resistance and metastasis, and the effects of neoadjuvant therapy on tumor hypoxia remain unclear. The current study aimed to evaluate the expressions of hypoxia-inducible factor-1 alpha (HIF1α) and hypoxia-inducible factor-2 alpha (HIF-2α) in advanced breast cancer cells following neoadjuvant treatment and their correlation with clinical characteristics. In total, 48 breast cancer specimens were collected before and after neoadjuvant therapy (28 treated with chemotherapy, 20 with hormonal therapy). Total RNA was isolated from 50 mg specimens. The mRNA levels of HIF-1α and HIF-2α were measured using qRT-PCR. The 18S rRNA was used as housekeeping gene. This study demonstrates that HIF-2α mRNA expression was significantly lower than those before therapy, whereas that of HIF-1α remained unchanged. We categorized the data based on clinical characteristics, and found that the increased expressio...
Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter?
Breast cancer research : BCR, 2004
Hypoxia-inducible factor 1 alpha (hif-1alpha) furnishes tumor cells with the means of adapting to stress parameters like tumor hypoxia and promotes critical steps in tumor progression and aggressiveness. We investigated the role of hif-1alpha expression in patients with node-positive breast cancer. Tumor samples from 77 patients were available for immunohistochemistry. The impact of hif-1alpha immunoreactivity on survival endpoints was determined by univariate and multivariate analyses, and correlations to clinicopathological characteristics were determined by cross-tabulations. hif-1alpha was expressed in 56% (n = 43/77) of the patients. Its expression correlated with progesterone receptor negativity (P = 0.002). The Kaplan-Meier curves revealed significantly shorter distant metastasis-free survival (DMFS) (P = 0.04, log-rank) and disease-free survival (DFS) (P = 0.04, log-rank) in patients with increased hif-1alpha expression. The difference in overall survival (OS) did not attain...
Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-A subunits HIF-1A and HIF-2A in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1A is not clear-cut and that of HIF-2A is largely unknown.Using IHC analyses of HIF-1A, HIF-2A, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-A subunits in relation to established clinicopathologic variables, VEGF expression, and survival.HIF-1 A and HIF-2A protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients.To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-A protein and HIF-A and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-A subunits by...
Cancer Research, 2008
Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-A subunits HIF-1A and HIF-2A in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1A is not clear-cut and that of HIF-2A is largely unknown. Using IHC analyses of HIF-1A, HIF-2A, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-A subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1A and HIF-2A protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-A protein and HIF-A and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-A subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1A and HIF-2A protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1A and HIF-2A associated to high VEGF expression. HIF-2A expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1A did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2A remained accumulated, whereas HIF-1A protein levels decreased, in agreement with the oxygen level and timedependent induction of HIFs recently reported in neuroblastoma. [Cancer Res 2008;68(22):9212-20]
Purpose: To investigate the relationship of hypoxia-inducible factor-1a (HIF-1a) tumor expression in predicting the response to epirubicin and disease-free survival (DFS) in patients with breast cancer enrolled in a single institution trial of primary anthracycline and tamoxifen therapy. Experimental Design: The expression of HIF-1awas assessed by immunohistochemistry in 187 patients withT2-4 N0-1breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin + tamoxifen as primary systemic treatment. All patients postoperatively received four cycles of the four weekly i.v. CMF regimen (cyclophosphamide, methotrexate, and 5-fluorouracil). Patients with estrogen receptor (ER)-positive primary tumors also underwent 5 years of treatment with adjuvant tamoxifen. Carbonic anhydrase IX (CAIX)was also scored as a marker of HIF activity. Results: Overall response to therapy progressively decreased with increasing tumor HIF-1a (P < 0.05), an...
Eurasian Chem. Commun, 2022
Hypoxemia means low levels of oxygen in the blood and it alters cancer cell metabolism and causes multiple intracellular signaling pathways. Investigate hypoxia status by measuring the concentration of HIF-1α as a prognostic factor of hypoxia and its relation to tumor suppressor protein p53, estradiol, tumor grade, tumor size, and lymph node metastases of adult female with breast cancer. This study is a case control study which includes sixty-five adult female patients with breast mass. Out of 65 patients, a 44 (68%) were with fibroadenoma in the age range of 18-42 (32.55±6.40) and the other 21 (32%) cases with breast cancer type invasive ductal carcinoma (IDC) aged 32-80 (56± 14.4). Most IDC cases were in grade III and sizes T2 and T3. The other 50 healthy females, as a control group were in mean age of 44.56±16.85. Preoperative blood samples were collected for biochemical analysis by the ELISA method. A significant elevation in serum HIF-1α, P53 and E2 (p<0.001) in IDC cases as compared to fibroadenoma and the control group, there was a positive relation between HIF-1α, P53, and E2. HIF-1 α, P53, and E2 were significantly elevated in the patients with grade III and tumor stage T3 than grade II and stages T2 and T1. A significant elevation was found in the subgroup of positive LNM for all preoperative serum levels of parameters compared with the negative LNM patients group. HIF-1α, p53, and E2 were useful markers of invasion depth of tumor or LNM in breast cancer staging and the interactions between HIF-1α, p53, and E2 signaling pathways may be of major clinical significance in cancer therapies through targeting the lowering of severity of hypoxia and angiogenesis. KEYWORDS Hypoxia; breast cancer; invasive ductal carcinoma; HIF-1α, tumor suppression protein p53; estradiol and lymph node metastases.
Journal of Clinical Pathology, 2005
Background: Intratumorous hypoxia triggers a broad cellular response mediated by the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1a concentrations increase during breast carcinogenesis, and are associated with poor prognosis. An earlier study noted two HIF-1a overexpression patterns: diffuse scattered throughout the tissue and confined to perinecrotic cells. Aims: To investigate the prognostic impact of these different HIF-1a overexpression patterns in relation to its downstream effectors carbonic anhydrase (CA) IX and glucose transporter 1 (GLUT-1). Methods: HIF-1a, CA IX, and GLUT-1 expression was studied by immunohistochemistry, including double staining for CA IX and HIF-1a. Clinical data included disease free survival, lymph node status, and tumour size. Results: HIF-1a overexpression (44% of cases) had a perinecrotic (13.5%) or diffuse staining pattern (30.5%). CA IX expression was detectable in 12.5% of breast cancers, whereas GLUT-1 expression was seen in 29%, with both showing perinecrotic membrane staining. Perinecrotic HIF-1a overexpression was highly associated with CA IX and GLUT-1 overexpression, and double staining for HIF-1a and CA IX showed strong expression in the same cells. Diffusely overexpressed HIF-1a was not associated with CA IX or GLUT-1 expression. Patients with diffuse HIF-1a staining had a significantly better prognosis than patients with perinecrotically overexpressed HIF-1a. Conclusions: Different regulation pathways of HIF-1a overexpression exist in breast cancer: (1) hypoxia induced, perinecrotic HIF-1a overexpression with strong expression of hypoxia associated genes (CA IX and GLUT-1), which is associated with a poor prognosis; and (2) diffuse HIF-1a overexpression lacking major hypoxia associated downstream effects, resulting in a more favourable prognosis.