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Interaction of Naloxone and Estrogen Receptor in Breast Cancer

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Morphine and Metastasis

Abstract

Majority of breast cancers are estrogen receptor (ER) positive. Due to resistance to known ER-based therapies, novel treatment targets and drugs are required to effectively treat ER-positive breast cancer. Opioids are often used to treat pain in breast cancer and promote tumor growth and metastases in rodent studies. Opioid receptor (OR) antagonists, such as naloxone, naltrexone and methylnaltrexone inhibit cancer progression and metastases. All three antagonists share structural similarities with the estrogen, 17β-estradiol (E2), and are therefore capable of binding to ER. Naloxone inhibits E2-induced human MCF-7 breast cancer cell proliferation and MAPK/ERK signaling. Additionally, naloxone also attenuates the activation of membrane bound/cytoplasmic ER and phosphorylation of the epidermal growth factor receptor. Naloxone blocks the E2-induced ER activation by precluding its binding to the co-activator and by directly competing with E2 for binding to ER. In addition to these direct interactions with ER, naloxone prevents the cross-talk of ER with mu opioid receptor (MOR), suggesting that activation of MOR may contribute to E2-induced ER activation. Since naloxone and structurally similar OR antagonists inhibit cancer progression and metastases, OR antagonists can be potentially developed for breast cancer treatment.

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Abbreviations

E2:

17β-estradiol

AF1:

activation-function 1

AF2:

activation-function 2

AI:

aromatase inhibitor

cAMP:

cyclic adenosine monophosphate

EGFR:

epidermal growth factor receptor

ER:

estrogen receptor

ERE:

estrogen response element

Gi-GPCRs:

inhibitory regulated-G protein coupled receptors

LBD:

ligand-binding domain

MNTX:

methylnaltrexone

MAPK/ERK:

mitogen activated protein kinase/extracellular signal-regulated kinase

Nal:

naloxone

NTX:

naltrexone

NOP:

nociceptin/orphanin FQ receptor

OR:

opioid receptor

PI3K:

phosphatidylinositol 3-kinase

Akt:

protein kinase B

SERMs:

selective ER modulators

VEGFR2:

vascular endothelial growth factor receptor 2

DOR:

δ opioid receptor

KOR:

κ opioid receptor

MOR:

μ opioid receptor

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Acknowledgements

The authors thank Ms Carol Taubert for manuscript preparation and figures. This work was supported by National Institutes of Health Grant numbers CA109582, HL068802 and HL103733.

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Authors and Affiliations

  1. Department of Medicine – Hematology, Oncology and Transplantation and Vascular Biology Center, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN, 55455, USA

    Katherine N. H. Johnson & Kalpna Gupta Ph.D.

  2. Astraea Therapeutics, LLC, 320 Logue Avenue, Suite 142, Mountain View, CA, 94043, USA

    Nurulain Zaveri Ph.D.

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  1. Katherine N. H. Johnson
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  2. Nurulain Zaveri Ph.D.
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  3. Kalpna Gupta Ph.D.
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Correspondence to Kalpna Gupta Ph.D. .

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  1. , School of Pharmacy, University of Queensland, Cornwall Street 20, Woolloongabba, QLD4102, Australia

    Marie-Odile Parat

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Johnson, K.N.H., Zaveri, N., Gupta, K. (2013). Interaction of Naloxone and Estrogen Receptor in Breast Cancer. In: Parat, MO. (eds) Morphine and Metastasis. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5678-6_2

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