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Loss of membranous VEGFR1 expression is associated with an adverse phenotype and shortened survival in breast cancer.

Lebok P, Huber J, Burandt EC, Lebeau A, Marx AH, Terracciano L, Heilenkötter U, Jänicke F, Müller V, Paluchowski P, Geist S, Wilke C, Simon R, Sauter G, Quaas A - Mol Med Rep (2016)

Bottom Line: Strong staining was significantly associated with estrogen receptor and progesterone receptor expression, but was inversely associated with advanced tumor stage (P=0.0431), high Bloom-Richardson-Ellis Score for Breast Cancer grade and low Ki67 labeling index (both P<0.0001).Cancers with moderate to strong (high) VEGFR1 expression were associated with significantly improved overall survival, as compared with tumors exhibiting negative or weak (low) expression (P=0.0015).In addition, reduced or lost VEGFR1 expression may serve as a marker for poor prognosis in patients with breast cancer, who might not optimally benefit from endocrine therapy.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, University Medical Centre Hamburg‑Eppendorf, D‑20246 Hamburg, Germany.

ABSTRACT
Angiogenesis is a key process in tumor growth and progression, which is controlled by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). In order to better understand the prevalence and prognostic value of VEGFR1 expression in breast cancer, a tissue microarray containing >2,100 breast cancer specimens, with clinical follow‑up data, was analyzed by immunohistochemistry using an antibody directed against the membrane‑bound full‑length receptor protein. The results demonstrated that membranous VEGFR1 staining was detected in all (5 of 5) normal breast specimens. In carcinoma specimens, membranous staining was negative in 3.1%, weak in 6.3%, moderate in 10.9%, and strong in 79.7% of the 1,630 interpretable tissues. Strong staining was significantly associated with estrogen receptor and progesterone receptor expression, but was inversely associated with advanced tumor stage (P=0.0431), high Bloom-Richardson-Ellis Score for Breast Cancer grade and low Ki67 labeling index (both P<0.0001). Cancers with moderate to strong (high) VEGFR1 expression were associated with significantly improved overall survival, as compared with tumors exhibiting negative or weak (low) expression (P=0.0015). This association was also detected in the subset of nodal‑positive cancers (P=0.0018), and in the subset of 185 patients who had received tamoxifen as the sole therapy (P=0.001). In conclusion, these data indicated that membrane‑bound VEGFR1 is frequently expressed in normal and cancerous breast epithelium. In addition, reduced or lost VEGFR1 expression may serve as a marker for poor prognosis in patients with breast cancer, who might not optimally benefit from endocrine therapy.

No MeSH data available.


Related in: MedlinePlus

Association between VEGFR1) immunostaining levels and cell proliferation, as determined using the Ki67 labeling index (LI) (P<0.0001). Box plots show 1st, 2nd (median) and 3rd quartile. Whiskers indicate 3rd quartile + 1.5× interquartile range or 1st quartile − 1.5× interquartile range. VEGFR1, vascular endothelial growth factor receptor 1; IHC, immunohistochemistry.
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f2-mmr-14-02-1443: Association between VEGFR1) immunostaining levels and cell proliferation, as determined using the Ki67 labeling index (LI) (P<0.0001). Box plots show 1st, 2nd (median) and 3rd quartile. Whiskers indicate 3rd quartile + 1.5× interquartile range or 1st quartile − 1.5× interquartile range. VEGFR1, vascular endothelial growth factor receptor 1; IHC, immunohistochemistry.

Mentions: VEGFR1 immunostaining was located in the membrane, and sometimes also the cytoplasm of luminal epithelial cells. Five samples of normal breast epithelium included in the tissue microarray exhibited strong VEGFR1 staining. Cancer cells typically exhibited strong staining compared with the staining intensity observed in the normal breast samples: Staining was strong in 1,299 (79.7%), moderate in 178 (10.9%), weak in 102 (6.3%) and negative in 51 (3.1%), of the 1,630 interpretable cancers. Representative images of VEGFR1 staining in normal and cancerous breast tissues are presented in Fig. 1. VEGFR1 staining levels were comparable (70–90% with strong staining) in the majority of different histological subtypes, apart from medullary cancers, which exhibited a significantly lower fraction of strongly VEGFR1-positive tumors (50%, P<0.0002), as compared with carcinoma of no special type (NST). In addition, VEGFR1 staining was inversely associated with tumor stage (P=0.0431) and BRE grade (P<0.0001), although the difference in numbers was only small. Staining levels were unrelated to the presence of lymph node metastases. Cell proliferation was previously determined immunohistochemically using the Ki67 labeling index (LI) (13). An inverse association was detected between VEGFR1 staining and cell proliferation: The average Ki67LI increased from 26.5% in 1,135 cancer specimens with strong VEGFR1 staining to 33.1% in 46 tumors lacking detectable VEGFR1 staining (P<0.0001; Fig. 2). Strong VEGFR1 immunostaining was also associated with positive ER and PR status and the triple negative category (all P<0.0001); however, VEGFR staining was unrelated to amplifications in HER2, CCND1 or MYC. The results are summarized in Table I. A multivariate analysis of overall survival demonstrated that VEGFR1 staining had non-significant impact on hazard ratio (Table II).


Loss of membranous VEGFR1 expression is associated with an adverse phenotype and shortened survival in breast cancer.

Lebok P, Huber J, Burandt EC, Lebeau A, Marx AH, Terracciano L, Heilenkötter U, Jänicke F, Müller V, Paluchowski P, Geist S, Wilke C, Simon R, Sauter G, Quaas A - Mol Med Rep (2016)

Association between VEGFR1) immunostaining levels and cell proliferation, as determined using the Ki67 labeling index (LI) (P<0.0001). Box plots show 1st, 2nd (median) and 3rd quartile. Whiskers indicate 3rd quartile + 1.5× interquartile range or 1st quartile − 1.5× interquartile range. VEGFR1, vascular endothelial growth factor receptor 1; IHC, immunohistochemistry.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940099&req=5

f2-mmr-14-02-1443: Association between VEGFR1) immunostaining levels and cell proliferation, as determined using the Ki67 labeling index (LI) (P<0.0001). Box plots show 1st, 2nd (median) and 3rd quartile. Whiskers indicate 3rd quartile + 1.5× interquartile range or 1st quartile − 1.5× interquartile range. VEGFR1, vascular endothelial growth factor receptor 1; IHC, immunohistochemistry.
Mentions: VEGFR1 immunostaining was located in the membrane, and sometimes also the cytoplasm of luminal epithelial cells. Five samples of normal breast epithelium included in the tissue microarray exhibited strong VEGFR1 staining. Cancer cells typically exhibited strong staining compared with the staining intensity observed in the normal breast samples: Staining was strong in 1,299 (79.7%), moderate in 178 (10.9%), weak in 102 (6.3%) and negative in 51 (3.1%), of the 1,630 interpretable cancers. Representative images of VEGFR1 staining in normal and cancerous breast tissues are presented in Fig. 1. VEGFR1 staining levels were comparable (70–90% with strong staining) in the majority of different histological subtypes, apart from medullary cancers, which exhibited a significantly lower fraction of strongly VEGFR1-positive tumors (50%, P<0.0002), as compared with carcinoma of no special type (NST). In addition, VEGFR1 staining was inversely associated with tumor stage (P=0.0431) and BRE grade (P<0.0001), although the difference in numbers was only small. Staining levels were unrelated to the presence of lymph node metastases. Cell proliferation was previously determined immunohistochemically using the Ki67 labeling index (LI) (13). An inverse association was detected between VEGFR1 staining and cell proliferation: The average Ki67LI increased from 26.5% in 1,135 cancer specimens with strong VEGFR1 staining to 33.1% in 46 tumors lacking detectable VEGFR1 staining (P<0.0001; Fig. 2). Strong VEGFR1 immunostaining was also associated with positive ER and PR status and the triple negative category (all P<0.0001); however, VEGFR staining was unrelated to amplifications in HER2, CCND1 or MYC. The results are summarized in Table I. A multivariate analysis of overall survival demonstrated that VEGFR1 staining had non-significant impact on hazard ratio (Table II).

Bottom Line: Strong staining was significantly associated with estrogen receptor and progesterone receptor expression, but was inversely associated with advanced tumor stage (P=0.0431), high Bloom-Richardson-Ellis Score for Breast Cancer grade and low Ki67 labeling index (both P<0.0001).Cancers with moderate to strong (high) VEGFR1 expression were associated with significantly improved overall survival, as compared with tumors exhibiting negative or weak (low) expression (P=0.0015).In addition, reduced or lost VEGFR1 expression may serve as a marker for poor prognosis in patients with breast cancer, who might not optimally benefit from endocrine therapy.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, University Medical Centre Hamburg‑Eppendorf, D‑20246 Hamburg, Germany.

ABSTRACT
Angiogenesis is a key process in tumor growth and progression, which is controlled by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). In order to better understand the prevalence and prognostic value of VEGFR1 expression in breast cancer, a tissue microarray containing >2,100 breast cancer specimens, with clinical follow‑up data, was analyzed by immunohistochemistry using an antibody directed against the membrane‑bound full‑length receptor protein. The results demonstrated that membranous VEGFR1 staining was detected in all (5 of 5) normal breast specimens. In carcinoma specimens, membranous staining was negative in 3.1%, weak in 6.3%, moderate in 10.9%, and strong in 79.7% of the 1,630 interpretable tissues. Strong staining was significantly associated with estrogen receptor and progesterone receptor expression, but was inversely associated with advanced tumor stage (P=0.0431), high Bloom-Richardson-Ellis Score for Breast Cancer grade and low Ki67 labeling index (both P<0.0001). Cancers with moderate to strong (high) VEGFR1 expression were associated with significantly improved overall survival, as compared with tumors exhibiting negative or weak (low) expression (P=0.0015). This association was also detected in the subset of nodal‑positive cancers (P=0.0018), and in the subset of 185 patients who had received tamoxifen as the sole therapy (P=0.001). In conclusion, these data indicated that membrane‑bound VEGFR1 is frequently expressed in normal and cancerous breast epithelium. In addition, reduced or lost VEGFR1 expression may serve as a marker for poor prognosis in patients with breast cancer, who might not optimally benefit from endocrine therapy.

No MeSH data available.


Related in: MedlinePlus