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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 intratumoural levels related to estrogen receptor status among postmenopausal women.Geometric mean with 95% confidence intervals of EGFR/HER1, HER2, HER3 and HER4 levels in estrogen receptor positive (ER+) and ER negative (-) HER2 non-amplified tumours from postmenopausal women. Significant differences between ER+ and ER- tumours are presented using the Mann-Whitney U test.
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pone-0074618-g004: HER1-4 and NRG1 intratumoural levels related to estrogen receptor status among postmenopausal women.Geometric mean with 95% confidence intervals of EGFR/HER1, HER2, HER3 and HER4 levels in estrogen receptor positive (ER+) and ER negative (-) HER2 non-amplified tumours from postmenopausal women. Significant differences between ER+ and ER- tumours are presented using the Mann-Whitney U test.

Mentions: From the subgroup of postmenopausal women, HER3 (P=0.004) and HER4 (P=0.024) were higher among ER+ as compared to ER- tumours (Figure 4). In addition, HER2 (r=0.525, P=0.044, Figure 5A) and HER3 (r=0.707, P=0.003, Figure 5B) correlated positively with ESR1 expression levels in postmenopausal women, and there was a correlation between intratumoural HER3 and E2 levels (r=0.544, P= 0.007, Table 5). Taken together, these data indicate breast cancer tissue HER3 and, potentially, HER2 and HER4 to be associated with estrogen stimulation.


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 intratumoural levels related to estrogen receptor status among postmenopausal women.Geometric mean with 95% confidence intervals of EGFR/HER1, HER2, HER3 and HER4 levels in estrogen receptor positive (ER+) and ER negative (-) HER2 non-amplified tumours from postmenopausal women. Significant differences between ER+ and ER- tumours are presented using the Mann-Whitney U test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3750010&req=5

pone-0074618-g004: HER1-4 and NRG1 intratumoural levels related to estrogen receptor status among postmenopausal women.Geometric mean with 95% confidence intervals of EGFR/HER1, HER2, HER3 and HER4 levels in estrogen receptor positive (ER+) and ER negative (-) HER2 non-amplified tumours from postmenopausal women. Significant differences between ER+ and ER- tumours are presented using the Mann-Whitney U test.
Mentions: From the subgroup of postmenopausal women, HER3 (P=0.004) and HER4 (P=0.024) were higher among ER+ as compared to ER- tumours (Figure 4). In addition, HER2 (r=0.525, P=0.044, Figure 5A) and HER3 (r=0.707, P=0.003, Figure 5B) correlated positively with ESR1 expression levels in postmenopausal women, and there was a correlation between intratumoural HER3 and E2 levels (r=0.544, P= 0.007, Table 5). Taken together, these data indicate breast cancer tissue HER3 and, potentially, HER2 and HER4 to be associated with estrogen stimulation.

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