The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion

Cindy Pon, Jonathan Robert David Lane, Erica Kate Sloan, Michelle Halls

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

Abstract

Activation of the sympathetic nervous system by stress increases breast cancer metastasis in vivo. Preclinical studies suggest that stress activates β-adrenoceptors (βARs) to enhance metastasis from primary tumors and that β-blockers may be protective in breast cancer. However, the subtype of βAR that mediates this effect, as well as the signaling mechanisms underlying increased tumor cell dissemination, remain unclear. We show that the β2AR is the only functionally relevant bAR subtype in the highly metastatic human breast cancer cell line MDA-MB-231HM. β2AR activation results in elevated cAMP (formoterol pEC50 9.86 ± 0.32), increased intracellular Ca2+ (formoterol pEC50 8.20 ± 0.33) and reduced phosphorylated ERK (pERK; formoterol pIC50 11.62 ± 0.31). We demonstrate that a highly amplified positive feedforward loop between the cAMP and Ca2+ pathways is responsible for efficient inhibition of basal pERK. Importantly, activation of the β2AR increased invasion (formoterol area under the curve [AUC] relative to vehicle: 1.82 ± 0.36), which was dependent on the cAMP/Ca2+ loop (formoterol AUC in the presence of 2959-dideoxyadenosine 0.64 ± 0.03, or BAPTA-AM0.45 ± 0.23) but independent of inhibition of basal pERK1/2 (vehicle AUC with U0126 0.60 ± 0.30). Specifically targeting the positive feedforward cAMP/Ca2+ loop may be beneficial for the development of therapeutics to slow disease progression in patients with breast cancer.
Original languageEnglish
Pages (from-to)1144-1154
Number of pages11
JournalFASEB Journal
Volume30
Issue number3
DOIs
Publication statusPublished - 2016

Keywords

  • Adrenergic receptor
  • GPCR
  • Metastasis
  • Stress

Cite this

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title = "The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion",
abstract = "Activation of the sympathetic nervous system by stress increases breast cancer metastasis in vivo. Preclinical studies suggest that stress activates β-adrenoceptors (βARs) to enhance metastasis from primary tumors and that β-blockers may be protective in breast cancer. However, the subtype of βAR that mediates this effect, as well as the signaling mechanisms underlying increased tumor cell dissemination, remain unclear. We show that the β2AR is the only functionally relevant bAR subtype in the highly metastatic human breast cancer cell line MDA-MB-231HM. β2AR activation results in elevated cAMP (formoterol pEC50 9.86 ± 0.32), increased intracellular Ca2+ (formoterol pEC50 8.20 ± 0.33) and reduced phosphorylated ERK (pERK; formoterol pIC50 11.62 ± 0.31). We demonstrate that a highly amplified positive feedforward loop between the cAMP and Ca2+ pathways is responsible for efficient inhibition of basal pERK. Importantly, activation of the β2AR increased invasion (formoterol area under the curve [AUC] relative to vehicle: 1.82 ± 0.36), which was dependent on the cAMP/Ca2+ loop (formoterol AUC in the presence of 2959-dideoxyadenosine 0.64 ± 0.03, or BAPTA-AM0.45 ± 0.23) but independent of inhibition of basal pERK1/2 (vehicle AUC with U0126 0.60 ± 0.30). Specifically targeting the positive feedforward cAMP/Ca2+ loop may be beneficial for the development of therapeutics to slow disease progression in patients with breast cancer.",
keywords = "Adrenergic receptor, GPCR, Metastasis, Stress",
author = "Cindy Pon and Lane, {Jonathan Robert David} and Sloan, {Erica Kate} and Michelle Halls",
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doi = "10.1096/fj.15-277798",
language = "English",
volume = "30",
pages = "1144--1154",
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The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion. / Pon, Cindy; Lane, Jonathan Robert David; Sloan, Erica Kate; Halls, Michelle.

In: FASEB Journal, Vol. 30, No. 3, 2016, p. 1144-1154.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion

AU - Pon, Cindy

AU - Lane, Jonathan Robert David

AU - Sloan, Erica Kate

AU - Halls, Michelle

PY - 2016

Y1 - 2016

N2 - Activation of the sympathetic nervous system by stress increases breast cancer metastasis in vivo. Preclinical studies suggest that stress activates β-adrenoceptors (βARs) to enhance metastasis from primary tumors and that β-blockers may be protective in breast cancer. However, the subtype of βAR that mediates this effect, as well as the signaling mechanisms underlying increased tumor cell dissemination, remain unclear. We show that the β2AR is the only functionally relevant bAR subtype in the highly metastatic human breast cancer cell line MDA-MB-231HM. β2AR activation results in elevated cAMP (formoterol pEC50 9.86 ± 0.32), increased intracellular Ca2+ (formoterol pEC50 8.20 ± 0.33) and reduced phosphorylated ERK (pERK; formoterol pIC50 11.62 ± 0.31). We demonstrate that a highly amplified positive feedforward loop between the cAMP and Ca2+ pathways is responsible for efficient inhibition of basal pERK. Importantly, activation of the β2AR increased invasion (formoterol area under the curve [AUC] relative to vehicle: 1.82 ± 0.36), which was dependent on the cAMP/Ca2+ loop (formoterol AUC in the presence of 2959-dideoxyadenosine 0.64 ± 0.03, or BAPTA-AM0.45 ± 0.23) but independent of inhibition of basal pERK1/2 (vehicle AUC with U0126 0.60 ± 0.30). Specifically targeting the positive feedforward cAMP/Ca2+ loop may be beneficial for the development of therapeutics to slow disease progression in patients with breast cancer.

AB - Activation of the sympathetic nervous system by stress increases breast cancer metastasis in vivo. Preclinical studies suggest that stress activates β-adrenoceptors (βARs) to enhance metastasis from primary tumors and that β-blockers may be protective in breast cancer. However, the subtype of βAR that mediates this effect, as well as the signaling mechanisms underlying increased tumor cell dissemination, remain unclear. We show that the β2AR is the only functionally relevant bAR subtype in the highly metastatic human breast cancer cell line MDA-MB-231HM. β2AR activation results in elevated cAMP (formoterol pEC50 9.86 ± 0.32), increased intracellular Ca2+ (formoterol pEC50 8.20 ± 0.33) and reduced phosphorylated ERK (pERK; formoterol pIC50 11.62 ± 0.31). We demonstrate that a highly amplified positive feedforward loop between the cAMP and Ca2+ pathways is responsible for efficient inhibition of basal pERK. Importantly, activation of the β2AR increased invasion (formoterol area under the curve [AUC] relative to vehicle: 1.82 ± 0.36), which was dependent on the cAMP/Ca2+ loop (formoterol AUC in the presence of 2959-dideoxyadenosine 0.64 ± 0.03, or BAPTA-AM0.45 ± 0.23) but independent of inhibition of basal pERK1/2 (vehicle AUC with U0126 0.60 ± 0.30). Specifically targeting the positive feedforward cAMP/Ca2+ loop may be beneficial for the development of therapeutics to slow disease progression in patients with breast cancer.

KW - Adrenergic receptor

KW - GPCR

KW - Metastasis

KW - Stress

UR - http://www.fasebj.org/content/30/3/1144.full.pdf+html

U2 - 10.1096/fj.15-277798

DO - 10.1096/fj.15-277798

M3 - Article

VL - 30

SP - 1144

EP - 1154

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 3

ER -