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Clinical & Experimental Metastasis

, Volume 29, Issue 4, pp 315–325 | Cite as

Ubiquitous Brms1 expression is critical for mammary carcinoma metastasis suppression via promotion of apoptosis

  • Leah M. Cook
  • Xuemei Cao
  • Alexander E. Dowell
  • Michael T. Debies
  • Mick D. Edmonds
  • Benjamin H. Beck
  • Robert A. Kesterson
  • Renee A. Desmond
  • Andra R. Frost
  • Douglas R. HurstEmail author
  • Danny R. WelchEmail author
Research Paper

Abstract

Morbidity and mortality of breast cancer patients are drastically increased when primary tumor cells are able to spread to distant sites and proliferate to become secondary lesions. Effective treatment of metastatic disease has been limited; therefore, an increased molecular understanding to identify biomarkers and therapeutic targets is needed. Breast cancer metastasis suppressor 1 (BRMS1) suppresses development of pulmonary metastases when expressed in a variety of cancer types, including metastatic mammary carcinoma. Little is known of Brms1 function throughout the initiation and progression of mammary carcinoma. The goal of this study was to investigate mechanisms of Brms1-mediated metastasis suppression in transgenic mice that express Brms1 using polyoma middle T oncogene-induced models. Brms1 expression did not significantly alter growth of the primary tumors. When expressed ubiquitously using a β-actin promoter, Brms1 suppressed pulmonary metastasis and promoted apoptosis of tumor cells located in the lungs but not in the mammary glands. Surprisingly, selective expression of Brms1 in the mammary gland using the MMTV promoter did not significantly block metastasis nor did it promote apoptosis in the mammary glands or lung, despite MMTV-induced expression within the lungs. These results strongly suggest that cell type-specific over-expression of Brms1 is important for Brms1-mediated metastasis suppression.

Keywords

Metastasis BRMS1 PyMT Transgenic MMTV Ubiquitous Apoptosis Breast cancer Mouse Mammary Tumor microenvironment 

Abbreviations

BRMS1

Breast cancer metastasis suppressor 1

PyMT

Polyoma middle T antigen

MMTV

Mouse mammary tumor virus

CMV

Cytomegalovirus

Ubqs

Ubiquitous

DAB

3,3′-Diaminobenzidine

TUNEL

Terminal deoxynucleotidyl transferase dUTP nick end labeling

TdT

Terminal deoxynucleotidyl transferase

NFkB

Nuclear factor kappa B

HDAC

Histone deacetylase

Tg

Transgenic

Wt

Wild-type

Notes

Acknowledgments

We would like to thank Dr. Clinton Grubbs in the UAB Department of Pharmacology and Toxicology for processing and preparing all histology slides. We are grateful for the counsel of Drs. Terri Wood and Rosa Serra during the course of these studies. We also thank Dr. Monica Richert for aiding in early colony maintenance of our transgenic mice and members of the Welch and Hurst labs for critical reading of the manuscript. We apologize to those whose work could not be cited due to space limitations. This paper is published in partial fulfillment of the requirements of the doctoral dissertation of LMC. Grant Support: National Institutes of Health [CA87728 (DRW), CA134981 (DRW) and CA089019 (DRW & DRH], National Foundation for Cancer Research (DRW), and Susan G. Komen for the Cure [SAC11037] (DRW); UAB Cancer Prevention and Control Training Grant [CA47888] (LMC); American Cancer Society [RSG-11-259-01-CSM] (DRH). DRW is an Eminent Scholar of the Kansas Biosciences Authority. The Transgenic Mouse Facility and Biostatistics Shared Resources were supported by the UAB Comprehensive Cancer Center core grant P30 CA13148.

Conflict of interest

We certify there are no conflicts of interest.

Supplementary material

10585_2012_9452_MOESM1_ESM.tif (24.1 mb)
Supplemental Fig. 1 Lung tissues do not exhibit alterations in morphology or pathology of metastatic lesions. Lung specimens from Brms1 transgenic mice and control littermates were collected, FFPE, and 5μm sections were stained with H&E. There were no visible differences in lung histomorphology due to Brms1 overexpression. There were no visible differences in the pathology of metastatic lesions in Brms1Ubqs mice. All images were captured at 200x magnification, size bar = 50 μm (TIFF 24672 kb)
10585_2012_9452_MOESM2_ESM.tif (24.1 mb)
Supplemental Fig. 2 Organ tissues do not exhibit metastatic development or alterations in morphology. Tissue specimens from Brms1 transgenic mice and control littermates were collected, FFPE, and 5μm sections were stained with H&E. There were no visible differences in organ histomorphology due to Brms1 overexpression. There were no microscopic metastases detected. All images were captured at 200x magnification, size bar = 50 μm (TIFF 24670 kb)

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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Leah M. Cook
    • 1
  • Xuemei Cao
    • 1
    • 7
  • Alexander E. Dowell
    • 2
  • Michael T. Debies
    • 7
  • Mick D. Edmonds
    • 1
  • Benjamin H. Beck
    • 1
  • Robert A. Kesterson
    • 3
    • 6
  • Renee A. Desmond
    • 2
    • 6
  • Andra R. Frost
    • 1
    • 4
    • 6
  • Douglas R. Hurst
    • 1
    • 6
    Email author
  • Danny R. Welch
    • 1
    • 4
    • 5
    • 6
    • 7
    • 8
    Email author
  1. 1.Department of PathologyUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Department of MedicineUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.Department of GeneticsUniversity of Alabama at BirminghamBirminghamUSA
  4. 4.Department of Cell BiologyUniversity of Alabama at BirminghamBirminghamUSA
  5. 5.Department of Pharmacology and ToxicologyUniversity of Alabama at BirminghamBirminghamUSA
  6. 6.Comprehensive Cancer CenterUniversity of Alabama at BirminghamBirminghamUSA
  7. 7.Department of Cancer BiologyThe Kansas University Medical CenterKansas CityUSA
  8. 8.University of Kansas Cancer CenterThe Kansas University Medical CenterKansas CityUSA

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