BRMS1 suppresses breast cancer metastasis in multiple experimental models of metastasis by reducing solitary cell survival and inhibiting growth initiation

  • Benjamin D. Hedley
  • Kedar S. Vaidya
  • Pushar Phadke
  • Lisa MacKenzie
  • David W. Dales
  • Carl O. Postenka
  • Ian C. MacDonald
  • Ann F. Chambers
Research Paper

Abstract

The majority of breast cancer related deaths occur as a result of metastasis. The failure of effective treatments for metastasis is the underlying cause for this. Much remains unknown about the process of metastasis and how best to prevent or treat metastatic breast cancer. Therefore, a better understanding of the metastatic process is needed in order to determine effective therapeutic interventions to either eradicate, or slow down metastatic outgrowth of breast cancer. Metastasis is an inefficient process, however the ability of only a small number of cells to complete this process may have serious, life-threatening consequences. Little is known about whether expression of the metastasis suppressor breast cancer metastasis suppressor 1 (BRMS1) can suppress metastatic outgrowth in different organs in multiple experimental models of metastasis, or what effect BRMS1 expression has on the various steps in metastatic cascade. In this study we investigated the effect of BRMS1 expression on organ-specific metastasis. In addition, the steps in metastasis that are inhibited by BRMS1-expression were determined. In vivo, BRMS1 expression reduced metastatic burden to liver, bone, brain, and lung in mice by at least 75% (P < 0.05). Detailed quantitative analysis of the metastatic process in lung showed that BRMS1 expression significantly reduced the numbers of solitary single cells that survive after initial arrest within the lung microvasculature, and also inhibited the initiation of growth subsequent to arrest. In vitro, BRMS1 expression decreased cancer cell survival under stress conditions (hypoxia), increased anoikis, and decreased the ability of cancer cells to adhere. These novel findings demonstrate that BRMS1 is a potent suppressor of metastasis in multiple organs, and identify two steps in the metastatic process that are sensitive to inhibition by BRMS1.

Keywords

Adhesion Apoptosis Breast cancer Growth suppression Metastasis Metastasis suppressor 

Abbreviations

BRMS1

Breast cancer metastasis suppressor gene 1

H&E

Haematoxylin and eosin

HBSS

Hank’s buffered salt solution

RGB

Red green blue

SFM

Serum free media

PB

Phosphate buffer

PBS

Phosphate buffered saline

bgal

Beta-galactocidase

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Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Benjamin D. Hedley
    • 1
    • 2
  • Kedar S. Vaidya
    • 3
  • Pushar Phadke
    • 3
  • Lisa MacKenzie
    • 2
  • David W. Dales
    • 1
  • Carl O. Postenka
    • 1
  • Ian C. MacDonald
    • 2
    • 4
  • Ann F. Chambers
    • 1
    • 2
    • 4
    • 5
  1. 1.London Regional Cancer ProgramLondon Health Sciences CentreLondonCanada
  2. 2.Department of Medical Biophysics, Schulich School of Medicine and DentistryUniversity of Western OntarioLondonCanada
  3. 3.Department of Pathology and Comprehensive Cancer CentreUniversity of Alabama at BirminghamBirminghamUSA
  4. 4.Department of Oncology, Schulich School of Medicine and DentistryUniversity of Western OntarioLondonCanada
  5. 5.Department of Pathology, Schulich School of Medicine and DentistryUniversity of Western OntarioLondonCanada

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