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J Mammary Gland Biol Neoplasia. 2017 Mar;22(1):59-69. doi: 10.1007/s10911-017-9373-z. Epub 2017 Jan 26.

Reelin Deficiency Delays Mammary Tumor Growth and Metastatic Progression.

Author information

1
Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. ekhiale@ucla.edu.
2
Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA.
3
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
4
Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA, USA.
5
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
6
Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA.
7
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA.
8
Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA.
9
Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA.

Abstract

Reelin is a regulator of cell migration in the nervous system, and has other functions in the development of a number of non-neuronal tissues. In addition, alterations in reelin expression levels have been reported in breast, pancreatic, liver, gastric, and other cancers. Reelin is normally expressed in mammary gland stromal cells, but whether stromal reelin contributes to breast cancer progression is unknown. Herein, we used a syngeneic mouse mammary tumor transplantation model to examine the impact of host-derived reelin on breast cancer progression. We found that transplanted syngeneic tumors grew more slowly in reelin-deficient (rl Orl -/- ) mice and had delayed metastatic colonization of the lungs. Immunohistochemistry of primary tumors revealed that tumors grown in rl Orl -/- animals had fewer blood vessels and increased macrophage infiltration. Gene expression studies from tumor tissues indicate that loss of host-derived reelin alters the balance of M1- and M2-associated macrophage markers, suggesting that reelin may influence the polarization of these cells. Consistent with this, rl Orl -/- M1-polarized bone marrow-derived macrophages have heightened levels of the M1-associated cytokines iNOS and IL-6. Based on these observations, we propose a novel function for the reelin protein in breast cancer progression.

KEYWORDS:

4T1; Breast cancer; Reelin; Tumor-associated macrophage

PMID:
28124184
PMCID:
PMC5319436
DOI:
10.1007/s10911-017-9373-z
[Indexed for MEDLINE]
Free PMC Article

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