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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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HER2 tumour levels and classification of HER2 amplified and non-amplified cancers.A) Relative mRNA expression levels of HER2 in estrogen receptor positive (ER+; black bars) and ER negative (- ; white bars with asterisk) breast tumours from pre- and postmenopausal women. Tumours identified to be HER2 non-amplified (NA) and amplified (A) by MPLA are indicated. B) Relative HER4 levels in HER2 NA and A tumours. Significant difference between A and NA tumours is presented using the Mann-Whitney U test.
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pone-0074618-g001: HER2 tumour levels and classification of HER2 amplified and non-amplified cancers.A) Relative mRNA expression levels of HER2 in estrogen receptor positive (ER+; black bars) and ER negative (- ; white bars with asterisk) breast tumours from pre- and postmenopausal women. Tumours identified to be HER2 non-amplified (NA) and amplified (A) by MPLA are indicated. B) Relative HER4 levels in HER2 NA and A tumours. Significant difference between A and NA tumours is presented using the Mann-Whitney U test.

Mentions: The study population including 42 pre- and postmenopausal breast cancer patients with ER+ and ER- disease (invasive carcinomas) has been described in detail previously (Table 2 [18]). Breast cancer and normal tissue from the same breast were available from 39 of the 42 patients. Nine tumours were amplified (>2 alleles) for the HER2 gene (range 3-14 alleles) and one tumour was amplified for the EGFR/HER1 gene. Tumours harbouring an elevated number of HER2 alleles in general presented high mRNA expression levels of HER2 (Figure 1A). Even though both ER+ (P=0.002) and ER- (P=0.001) tumours exhibit a significant higher HER2 mRNA levels in HER2 amplified compared to non-amplified tumours, the difference in HER2 mRNA levels between amplified and non-amplified tumours were most evident among ER- tumours (Figure 1A). Interestingly, we also observed a decreased HER4 mRNA expression in tumours with HER2 gene amplification compared to non-amplified tumours (P=0.024, Figure 1B) suggesting that increased levels of HER2 may be associated with HER4 suppression.


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)

HER2 tumour levels and classification of HER2 amplified and non-amplified cancers.A) Relative mRNA expression levels of HER2 in estrogen receptor positive (ER+; black bars) and ER negative (- ; white bars with asterisk) breast tumours from pre- and postmenopausal women. Tumours identified to be HER2 non-amplified (NA) and amplified (A) by MPLA are indicated. B) Relative HER4 levels in HER2 NA and A tumours. Significant difference between A and NA tumours is 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-g001: HER2 tumour levels and classification of HER2 amplified and non-amplified cancers.A) Relative mRNA expression levels of HER2 in estrogen receptor positive (ER+; black bars) and ER negative (- ; white bars with asterisk) breast tumours from pre- and postmenopausal women. Tumours identified to be HER2 non-amplified (NA) and amplified (A) by MPLA are indicated. B) Relative HER4 levels in HER2 NA and A tumours. Significant difference between A and NA tumours is presented using the Mann-Whitney U test.
Mentions: The study population including 42 pre- and postmenopausal breast cancer patients with ER+ and ER- disease (invasive carcinomas) has been described in detail previously (Table 2 [18]). Breast cancer and normal tissue from the same breast were available from 39 of the 42 patients. Nine tumours were amplified (>2 alleles) for the HER2 gene (range 3-14 alleles) and one tumour was amplified for the EGFR/HER1 gene. Tumours harbouring an elevated number of HER2 alleles in general presented high mRNA expression levels of HER2 (Figure 1A). Even though both ER+ (P=0.002) and ER- (P=0.001) tumours exhibit a significant higher HER2 mRNA levels in HER2 amplified compared to non-amplified tumours, the difference in HER2 mRNA levels between amplified and non-amplified tumours were most evident among ER- tumours (Figure 1A). Interestingly, we also observed a decreased HER4 mRNA expression in tumours with HER2 gene amplification compared to non-amplified tumours (P=0.024, Figure 1B) suggesting that increased levels of HER2 may be associated with HER4 suppression.

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