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Inverse regulation of EGFR/HER1 and HER2-4 in normal and malignant human breast tissue.

Flågeng MH, Knappskog S, Haynes BP, Lønning PE, Mellgren G - PLoS ONE (2013)

Bottom Line: Interestingly, HER3 as well as HER4 were higher among ER+ as compared to ER- tumours (P=0.004 and P=0.024, respectively).In contrast, EGFR/HER1 was downregulated in tumour compared to normal tissue (0.13-fold, P<0.001).In ER+ tumours from postmenopausal women, NRG1 levels correlated positively with EGFR/HER1 (r=0.606, P=0.002) and negatively to ESR1 (r=-0.769, P=0.003) and E2 levels (r=-0.542, P=0.020).

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.

ABSTRACT
Cross-talk between the estrogen and the EGFR/HER signalling pathways has been suggested as a potential cause of resistance to endocrine therapy in breast cancer. Here, we determined HER1-4 receptor and neuregulin-1 (NRG1) ligand mRNA expression levels in breast cancers and corresponding normal breast tissue from patients previously characterized for plasma and tissue estrogen levels. In tumours from postmenopausal women harbouring normal HER2 gene copy numbers, we found HER2 and HER4, but HER3 levels in particular, to be elevated (2.48, 1.30 and 22.27 -fold respectively; P<0.01 for each) compared to normal tissue. Interestingly, HER3 as well as HER4 were higher among ER+ as compared to ER- tumours (P=0.004 and P=0.024, respectively). HER2 and HER3 expression levels correlated positively with ER mRNA (ESR1) expression levels (r=0.525, P=0.044; r=0.707, P=0.003, respectively). In contrast, EGFR/HER1 was downregulated in tumour compared to normal tissue (0.13-fold, P<0.001). In addition, EGFR/HER1 correlated negatively to intra-tumour (r=-0.633, P=0.001) as well as normal tissue (r=-0.556, P=0.006) and plasma estradiol levels (r=-0.625, P=0.002), suggesting an inverse regulation between estradiol and EGFR/HER1 levels. In ER+ tumours from postmenopausal women, NRG1 levels correlated positively with EGFR/HER1 (r=0.606, P=0.002) and negatively to ESR1 (r=-0.769, P=0.003) and E2 levels (r=-0.542, P=0.020). Our results indicate influence of estradiol on the expression of multiple components of the HER system in tumours not amplified for HER2, adding further support to the hypothesis that cross-talk between these systems may be of importance to breast cancer growth in vivo.

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HER1-4 and NRG1 levels related to estrogen receptor status.Geometric mean with 95% confidence intervals of the HER-receptors and NRG1 in estrogen receptor positive (ER+) and ER negative (-) tumours (A) and intervals of tumour to normal tissue ratio (B) among all patients with HER2 non-amplified disease. Significant differences between ER+ and ER- tumours are presented using the Mann-Whitney U test.
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pone-0074618-g003: HER1-4 and NRG1 levels related to estrogen receptor status.Geometric mean with 95% confidence intervals of the HER-receptors and NRG1 in estrogen receptor positive (ER+) and ER negative (-) tumours (A) and intervals of tumour to normal tissue ratio (B) among all patients with HER2 non-amplified disease. Significant differences between ER+ and ER- tumours are presented using the Mann-Whitney U test.

Mentions: Among all HER2 non-amplified tumours, we found HER2 (P=0.026) in addition to HER3 (P=0.030) and HER4 (P=0.007) to be higher among ER+ as compared to ER- tumours (Figure 3A). Moreover, a higher tumour to normal tissue concentration ratio was observed for HER2 (P=0.042) as well as HER4 (P=0.012) among ER+ tumours as compared to ER- tumours (Figure 3B). In addition, both HER2 (r=0.547, P=0.001, data not shown) and HER4 (r=0.513, P=0.017) correlated positively with ESR1 expression levels in these HER2 non-amplified tumours including both pre- and postmenopausal women. ESR1 mRNA expression levels were obtained from a previous study were high ESR1 expression levels were associated with ER+ tumours [17].


Inverse regulation of EGFR/HER1 and HER2-4 in normal and malignant human breast tissue.

Flågeng MH, Knappskog S, Haynes BP, Lønning PE, Mellgren G - PLoS ONE (2013)

HER1-4 and NRG1 levels related to estrogen receptor status.Geometric mean with 95% confidence intervals of the HER-receptors and NRG1 in estrogen receptor positive (ER+) and ER negative (-) tumours (A) and intervals of tumour to normal tissue ratio (B) among all patients with HER2 non-amplified disease. Significant differences between ER+ and ER- tumours are presented using the Mann-Whitney U test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750010&req=5

pone-0074618-g003: HER1-4 and NRG1 levels related to estrogen receptor status.Geometric mean with 95% confidence intervals of the HER-receptors and NRG1 in estrogen receptor positive (ER+) and ER negative (-) tumours (A) and intervals of tumour to normal tissue ratio (B) among all patients with HER2 non-amplified disease. Significant differences between ER+ and ER- tumours are presented using the Mann-Whitney U test.
Mentions: Among all HER2 non-amplified tumours, we found HER2 (P=0.026) in addition to HER3 (P=0.030) and HER4 (P=0.007) to be higher among ER+ as compared to ER- tumours (Figure 3A). Moreover, a higher tumour to normal tissue concentration ratio was observed for HER2 (P=0.042) as well as HER4 (P=0.012) among ER+ tumours as compared to ER- tumours (Figure 3B). In addition, both HER2 (r=0.547, P=0.001, data not shown) and HER4 (r=0.513, P=0.017) correlated positively with ESR1 expression levels in these HER2 non-amplified tumours including both pre- and postmenopausal women. ESR1 mRNA expression levels were obtained from a previous study were high ESR1 expression levels were associated with ER+ tumours [17].

Bottom Line: Interestingly, HER3 as well as HER4 were higher among ER+ as compared to ER- tumours (P=0.004 and P=0.024, respectively).In contrast, EGFR/HER1 was downregulated in tumour compared to normal tissue (0.13-fold, P<0.001).In ER+ tumours from postmenopausal women, NRG1 levels correlated positively with EGFR/HER1 (r=0.606, P=0.002) and negatively to ESR1 (r=-0.769, P=0.003) and E2 levels (r=-0.542, P=0.020).

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.

ABSTRACT
Cross-talk between the estrogen and the EGFR/HER signalling pathways has been suggested as a potential cause of resistance to endocrine therapy in breast cancer. Here, we determined HER1-4 receptor and neuregulin-1 (NRG1) ligand mRNA expression levels in breast cancers and corresponding normal breast tissue from patients previously characterized for plasma and tissue estrogen levels. In tumours from postmenopausal women harbouring normal HER2 gene copy numbers, we found HER2 and HER4, but HER3 levels in particular, to be elevated (2.48, 1.30 and 22.27 -fold respectively; P<0.01 for each) compared to normal tissue. Interestingly, HER3 as well as HER4 were higher among ER+ as compared to ER- tumours (P=0.004 and P=0.024, respectively). HER2 and HER3 expression levels correlated positively with ER mRNA (ESR1) expression levels (r=0.525, P=0.044; r=0.707, P=0.003, respectively). In contrast, EGFR/HER1 was downregulated in tumour compared to normal tissue (0.13-fold, P<0.001). In addition, EGFR/HER1 correlated negatively to intra-tumour (r=-0.633, P=0.001) as well as normal tissue (r=-0.556, P=0.006) and plasma estradiol levels (r=-0.625, P=0.002), suggesting an inverse regulation between estradiol and EGFR/HER1 levels. In ER+ tumours from postmenopausal women, NRG1 levels correlated positively with EGFR/HER1 (r=0.606, P=0.002) and negatively to ESR1 (r=-0.769, P=0.003) and E2 levels (r=-0.542, P=0.020). Our results indicate influence of estradiol on the expression of multiple components of the HER system in tumours not amplified for HER2, adding further support to the hypothesis that cross-talk between these systems may be of importance to breast cancer growth in vivo.

Show MeSH
Related in: MedlinePlus