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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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Changes in HER1-4 and NRG1 expression levels from normal to tumour breast tissue.Individual mRNA levels of EGFR/HER1(A), HER2 (B), HER3 (C), HER4 (D) and NRG1 (E) from normal and tumour tissue from each postmenopausal patient.
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pone-0074618-g002: Changes in HER1-4 and NRG1 expression levels from normal to tumour breast tissue.Individual mRNA levels of EGFR/HER1(A), HER2 (B), HER3 (C), HER4 (D) and NRG1 (E) from normal and tumour tissue from each postmenopausal patient.

Mentions: Expression levels of EGFR/HER1, HER2, HER3, HER4 and NRG1 in normal and breast cancer tissue are presented in Table 3 and Figure 2. Comparing paired tumour and normal tissue samples, we found a significantly lower level of EGFR/HER1 in tumour compared to normal tissue both among premenopausal (8 of 8 patients, individual ratio 0.10 (95% CI: 0.047-0.23), P=0.012) as well as postmenopausal (22 of 22, individual ratio: 0.13; CI: 0.09-0.20, P<0.001) women. In contrast, HER2 and HER3 expression levels were higher in tumours compared to normal tissue. Thus, HER2 was elevated in 7 of 8 premenopausal tumours (individual ratio: 2.64; CI: 1.50-4.63, P=0.017) and HER3 in 8 of 8 individuals (individual ratio: 16.96; CI: 4.02-71.52, P=0.012). In postmenopausal tumours, HER2 was elevated in 19 of 22 (individual ratio: 2.48; CI: 1.70-3.65, P<0.001) and HER3 in 21 out of 22 (individual ratio: 22.27; CI: 9.03-54.92, P<0.001). HER4 expression levels were significantly higher in tumours compared to normal tissue among postmenopausal women only (17 of 22, individual ratio: 1.30 CI: 0.54-3.16, P=0.006). No significant difference in NRG1 levels between normal breast and cancer tissue was recorded.


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)

Changes in HER1-4 and NRG1 expression levels from normal to tumour breast tissue.Individual mRNA levels of EGFR/HER1(A), HER2 (B), HER3 (C), HER4 (D) and NRG1 (E) from normal and tumour tissue from each postmenopausal patient.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0074618-g002: Changes in HER1-4 and NRG1 expression levels from normal to tumour breast tissue.Individual mRNA levels of EGFR/HER1(A), HER2 (B), HER3 (C), HER4 (D) and NRG1 (E) from normal and tumour tissue from each postmenopausal patient.
Mentions: Expression levels of EGFR/HER1, HER2, HER3, HER4 and NRG1 in normal and breast cancer tissue are presented in Table 3 and Figure 2. Comparing paired tumour and normal tissue samples, we found a significantly lower level of EGFR/HER1 in tumour compared to normal tissue both among premenopausal (8 of 8 patients, individual ratio 0.10 (95% CI: 0.047-0.23), P=0.012) as well as postmenopausal (22 of 22, individual ratio: 0.13; CI: 0.09-0.20, P<0.001) women. In contrast, HER2 and HER3 expression levels were higher in tumours compared to normal tissue. Thus, HER2 was elevated in 7 of 8 premenopausal tumours (individual ratio: 2.64; CI: 1.50-4.63, P=0.017) and HER3 in 8 of 8 individuals (individual ratio: 16.96; CI: 4.02-71.52, P=0.012). In postmenopausal tumours, HER2 was elevated in 19 of 22 (individual ratio: 2.48; CI: 1.70-3.65, P<0.001) and HER3 in 21 out of 22 (individual ratio: 22.27; CI: 9.03-54.92, P<0.001). HER4 expression levels were significantly higher in tumours compared to normal tissue among postmenopausal women only (17 of 22, individual ratio: 1.30 CI: 0.54-3.16, P=0.006). No significant difference in NRG1 levels between normal breast and cancer tissue was recorded.

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