High frequency of HIF-1α overexpression in BRCA1 related breast cancer

Groep, Petra van der; Bouter, A; Menko, Fred H.; Wall, Elsken van der; Diest, Paul J. van

doi:10.1007/s10549-007-9817-z

Cited by 72 publications

(65 citation statements)

References 38 publications

(45 reference statements)

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“…Previous studies have shown that in breast cancer Glut-1 overexpression is associated with high histologic grade, high proliferative activity, poor differentiation, BRCA1-related breast cancer, ER negativity, PR negativity, and the basal-like subtype [24,25,26,27,33,47,52], and the results are consistent with those of this study. The expression of CAIX was associated with TNBC type (p = 0.012), high histologic grade (p = 0.019), and ER negativity (p = 0.008), and these results are consistent with previous studies showing that the expression of CAIX in breast cancer is correlated with a high histologic grade, BRCA1-related breast cancer, ER negativity, PR negativity, and the basal-like subtype [31,32,33,47]. The expression of Glut-1 and that of CAIX were associated with similar parameters, consistent with a previous study that showed a highly positive correlation between Glut1 expression and CAIX expression [30].…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies have suggested that the expression patterns of HIF-1α reflect different mechanisms. It has been reported that perinecrotic or focal patterns of expression reflect HIF-1α overexpression induced by severe hypoxia [47] and that diffuse patterns of expression reflect HIF-1α overexpression by HER-2 [46], HIF-1α gene amplification [48], or mutation [49] rather than hypoxia. In this study, we were unable to compare results directly with previous studies since a diffuse pattern of HIF-1α expression was not noted in more than 50% for any tumor.…”

Section: Discussionmentioning

confidence: 99%

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Metabolism-Related Proteins Are Differentially Expressed according to the Molecular Subtype of Invasive Breast Cancer Defined by Surrogate Immunohistochemistry

Choi

Jung

Koo³

2012

Pathobiology

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Objective: The purpose of this study was to investigate the expression of metabolism-related proteins such as Glut-1 and carbonic anhydrase IX (CAIX) according to breast cancer molecular subtype. Methods: We generated a tissue microarray of 276 breast cancer patients and performed immunohistochemical staining for known metabolism-related proteins, which were evaluated according to the molecular subtype. Results: The expression of IGF-1, MIF, and HIF-1α was correlated with the HER-2 type (p < 0.05). Glut-1 overexpression and CAIX expression were associated with TNBC type, especially with basal-like type, high histologic grade, estrogen receptor negativity, and progesterone receptor negativity (p < 0.05). The expression of Glut-1 and CAIX was correlated with statistical significance (p < 0.001). Conclusion: We identified different patterns of expression of metabolism-related proteins according to the molecular subtypes of breast cancer defined by surrogate immunohistochemistry. Increased expression of HIF-1α, IGF-1, and MIF was noted in HER-2 type breast cancer and increased expression of Glut-1 and CAIX was noted in TNBC type breast cancer, especially in the basal-like subtype, which exhibited a glycolytic and acid-resistant tumor phenotype.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Metabolism-Related Proteins Are Differentially Expressed according to the Molecular Subtype of Invasive Breast Cancer Defined by Surrogate Immunohistochemistry

Choi

Jung

Koo³

2012

Pathobiology

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“…Similarly, sporadic female breast cancers 6 showed a higher frequency of HIF1A positive tumors (50%) compared with sporadic male breast cancers in our study (28%), and comparable to the study by Kornegoor et al 18 (27%). A similar but less extreme difference is seen when comparing CA9 expression in male breast cancer and female breast cancer, 6,26 again in keeping with the findings of Kornegoor et al 18 We also only found seven cases (3%) that expressed both HIF1A and CA9. Although this is below the range seen in female breast cancer (11-23%), 6,27 it is not unexpected given the decreased staining of either marker when compared with female breast cancer and the known variability in HIF1A and CA9 half-lives.…”

Section: Discussionsupporting

confidence: 89%

Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer

et al. 2014

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Male breast cancer is poorly understood with a large proportion arising in the familial context particularly with the BRCA2 germline mutation. As phenotypic and genotypic differences between sporadic and familial male breast cancers have been noted, we investigated the importance of a hypoxic drive in these cancers as this pathway has been shown to be of importance in familial female breast cancer. Expression of two major hypoxiainduced proteins, the hypoxia-inducible factor-1a (HIF1A) and the carbonic anhydrase IX (CA9), examined within a large cohort including 61 familial (3 BRCA1, 28 BRCA2, 30 BRCAX) and 225 sporadic male breast cancers showed that 31% of all male breast cancers expressed either HIF1A (25%) and/or CA9 (8%) in the combined cohort. Expression of HIF1A correlated with an increased incidence of a second-major malignancy (P ¼ 0.04), histological tumor type (P ¼ 0.005) and basal phenotype (P ¼ 0.02). Expression of CA9 correlated with age (P ¼ 0.004) in sporadic cases and an increased tumor size (P ¼ 0.003). Expression of HIF1A was prognostic for disease-specific survival in sporadic male breast cancers (HR: 3.8, 95% CI: 1.5-9.8, P ¼ 0.006) but not within familial male breast cancer, whereas CA9 was only prognostic in familial male breast cancers (HR: 358.0, 95% CI: 9.3-13781.7, P ¼ 0.002) and not in sporadic male breast cancer. This study found that hypoxic drive is less prevalent in male breast cancer compared with female breast cancer, possibly due to a different breast microenvironment. The prognostic impact of HIF1A is greatest in sporadic male breast cancers with an alternate dominant mechanism for the oncogenic drivers suggested in high risk familial male breast cancers.

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“…30 Antigen retrieval for Glut-1 was carried out with epitope retrieval buffer 1, 20 min at 99 1C (AR9961; Leica Microsystems). The slides were incubated with the primary antibody Glut-1 for 15 min at room temperature and afterwards with the Bond refine polymer kit (DS9800; Leica Microsystems).…”

Section: Fibrotic Focusmentioning

confidence: 99%

Fibrotic focus and hypoxia in male breast cancer

et al. 2012

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Fibrotic focus is a scar-like lesion near the center of a carcinoma and has been associated with high-grade, lymph node metastases and poor survival in female breast cancers. Hypoxia is suggested to be the crucial link between fibrotic focus and aggressive tumor phenotype and is also itself a poor prognostic marker. We here set out to study fibrotic focus and hypoxia in male breast cancer for the first time. In a group of 134 male breast cancer patients, the presence and size of a fibrotic focus and the expression of three hypoxia-related immunohistochemical stainings, hypoxia-inducible factor-1a, carbonic anhydrase IX and Glut-1 were studied in correlation with clinicopathological features and prognosis. Fibrotic focus was seen in 25% of the male breast cancer cases and was correlated with hypoxia-inducible factor-1a overexpression (P ¼ 0.023), high grade (P ¼ 0.005), high mitotic activity (P ¼ 0.005) and lymph node metastases (P ¼ 0.037). Hypoxia-inducible factor-1a-positive tumors were more often high grade (P ¼ 0.003) and HER2 amplified (P ¼ 0.005). Glut-1 expression was also more common in grade 3 tumors (P ¼ 0.038), but no association between carbonic anhydrase IX and any clinicopathological feature was found. Fibrotic focus 48 mm and hypoxia-inducible factor-1a overexpression were correlated with decreased patients' outcome (P ¼ 0.035 and 0.008, respectively). Hypoxia-inducible factor1a overexpression was an independent and the most powerful predictor of survival in multivariate analysis (P ¼ 0.029; hazard ratio 2.5). In conclusion, the presence of a fibrotic focus is associated with hypoxia-inducible factor-1a overexpression, and both are associated with aggressive tumor phenotype and poor survival in male breast cancer. These markers seem to have similar clinical importance as previously reported in female breast cancer. Modern Pathology (2012) 25, 1397-1404; doi:10.1038/modpathol.2012.101; published online 8 June 2012Keywords: fibrotic focus; hypoxia; male breast cancer; prognosis Male breast cancer is uncommon and represents o1% of all breast cancers. 1 Large series in male breast cancer are lacking and much of the knowledge is generalized from breast cancer in female subjects. The limited data published on male breast cancer indicate that there are genetic and phenotypic differences between male and female breast cancer. [2][3][4][5][6] Initially, prognosis in men was claimed to be poor with higher incidence of lymph node metastases at the time of discovery, but more recent studies showed that prognosis of male and female breast cancers corrected for stage and age is similar. [7][8][9] Although tumor size and lymph node status are independent prognosticators in male breast cancer, 9,10 there still is a need for more accurate outcome predictors of male breast cancer.A fibrotic focus is a scar-like lesion consisting of an area of mainly collagen and fibroblasts, often located near the center of a carcinoma. Fibrotic focus is associated with poor survival in female breast cancer and with high grade, hig...

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High frequency of HIF-1α overexpression in BRCA1 related breast cancer

Cited by 72 publications

References 38 publications

Metabolism-Related Proteins Are Differentially Expressed according to the Molecular Subtype of Invasive Breast Cancer Defined by Surrogate Immunohistochemistry

Metabolism-Related Proteins Are Differentially Expressed according to the Molecular Subtype of Invasive Breast Cancer Defined by Surrogate Immunohistochemistry

Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer

Fibrotic focus and hypoxia in male breast cancer

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