Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers

Abstract

While estrogens have been shown to modulate EGFR/HER-1 and HER-2/neu expression in experimental systems, the effects of estrogen deprivation on expression levels of the HER-receptors and the neuregulin (NRG)1 ligand in breast cancers remain unknown. Here, we measured EGFR/HER-1-4 and NRG1 mRNA in ER positive tumors from 85 postmenopausal breast cancer patients before and after two weeks (n=64) and three months (n=85) of primary treatment with an aromatase inhibitor (AI). In tumors lacking HER-2/neu amplification, quantitative real-time PCR analyses revealed EGFR/HER-1 and NRG1 to vary significantly between the three time points (before therapy, after 2 weeks and after 3 months on treatment; P≤0.001 for both). Pair-wise comparison revealed a significant increase in EGFR/HER-1 already during the first two weeks of treatment (P=0.049) with a further increase for both EGFR/HER-1 and NRG1 after 3 months on treatment (P≤0.001 and P=0.001 for both comparing values at 3 months to values at baseline and 2 weeks respectively). No difference between tumors responding versus non-responders was recorded. Further, no significant change in any parameter was observed among HER-2/neu amplified tumors. Analyzing components of the HER-2/neu PI3K/Akt downstream pathway, the PIK3CA H1047R mutation was associated with treatment response (P=0.035); however no association between either AKT phosphorylation status or PIK3CA gene mutations and EGFR/HER-1 or NRG1 expression levels were observed. Our results indicate primary AI treatment to modulate expression of HER-family members and the growth factor NRG1 in HER-2/neu non-amplified breast cancers in vivo. Potential implications to long term sensitivity warrants further investigations.

The Endocrine Disruptor Bisphenol A (BPA) Affects the Enteric Neurons Immunoreactive to Neuregulin 1 (NRG1) in the Enteric Nervous System of the Porcine Large Intestine

“…They are located in the mucosal layer, both in cells located in the submucosal layer identified as macrophages, as well as in the neuronal cells of the ENS [78,79] and they are involved in many processes including, among others, intestinal motility, inflammatory reactions, cell proliferation, regulation of mitochondrial function and protective processes (for review, see [80]). Since BPA is known as a ligand of the estrogen receptors, and previous studies also linked the levels of NRG 1 expression with endocrine resistance [81,82], the changes noted in the present study may result from endocrine disruption caused by BPA.…”

Relation among Aromatase P450 and Tumoral Growth in Human Prolactinomas

“…In EGFR- and HER2-overexpression transgenic models larger tumors appear that respond to tyrosine kinase inhibitors [ 68 ]. Although the relation among aromatase, estrogens, and EGFR have been studied in different tumors such as breast [ 69 ], endometrial [ 70 ], lung [ 71 ], and liver [ 72 ] tumors, among others, the relationship between EGFR and aromatase in pituitary gland or prolactinomas has not been well analyzed to date, but its participation should not be ruled out.…”

Protein Phosphatase-1 Regulates Expression of Neuregulin-1

“…While downstream signaling by NRG-1 proteins is well studied, transcriptional regulation of the NRG-1 gene is poorly understood. Chronic stress, exercise training, estrogen deprivation, vitamin D and antipsychotic drugs increase NRG-1 expression [16,17,18,19]. The only study that has characterized the NRG-1 promoter showed that it contained Sp1 and NF-κB binding sites and presumed to be activated by Sp1 and NF-κB factors [20].…”