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Mena invasive (MenaINV) and Mena11a isoforms play distinct roles in breast cancer cell cohesion and association with TMEM

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Abstract

Mena, an actin regulatory protein, functions at the convergence of motility pathways that drive breast cancer cell invasion and migration in vivo. The tumor microenvironment spontaneously induces both increased expression of the Mena invasive (MenaINV) and decreased expression of Mena11a isoforms in invasive and migratory tumor cells. Tumor cells with this Mena expression pattern participate with macrophages in migration and intravasation in mouse mammary tumors in vivo. Consistent with these findings, anatomical sites containing tumor cells with high levels of Mena expression associated with perivascular macrophages were identified in human invasive ductal breast carcinomas and called TMEM. The number of TMEM sites positively correlated with the development of distant metastasis in humans. Here we demonstrate that mouse mammary tumors generated from EGFP-MenaINV expressing tumor cells are significantly less cohesive and have discontinuous cell–cell contacts compared to Mena11a xenografts. Using the mouse PyMT model we show that metastatic mammary tumors express 8.7 fold more total Mena and 7.5 fold more MenaINV mRNA than early non-metastatic ones. Furthermore, MenaINV expression in fine needle aspiration biopsy (FNA) samples of human invasive ductal carcinomas correlate with TMEM score while Mena11a does not. These results suggest that MenaINV is the isoform associated with breast cancer cell discohesion, invasion and intravasation in mice and in humans. They also imply that MenaINV expression and TMEM score measure related aspects of a common tumor cell dissemination mechanism and provide new insight into metastatic risk.

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Abbreviations

EGF:

Epidermal growth factor

EGFP:

Enhanced green fluorescent protein

FACs:

Fluorescence activated cell sorting

FFPE:

Formalin-fixed paraffin-embedded

FNA:

Fine needle aspiration

IHC:

Immunohistochemistry

IF:

Immunofluorescence

IVI:

Intravital imaging

qRT-PCR:

Quantitative real time polymerase chain reaction

SCID:

Severe combined immunodeficiency

TMEM:

Tumor microenvironment for metastasis

APTC:

Average primary tumor cells

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Acknowledgments

We would like to thank Drs. Jeffery Segall, Diane Cox, Antonia Patsialou, and Daqian Sun for stimulating discussion and helpful suggestions. We also thank Drs. Sasis Sirikanjanapong, Jason Moss, and Zhong, as well as research associate Mrs. Felicia Juliano for assistance with FNA biopsy procedures, Dr. Jaya Sunkara for assistance with E-cadherin staining, and Dr. Olena Dorokhova for help with RNA extraction and cDNA synthesis. Many thanks to David Entenberg, and Jenny Tadros for their technical support, Einstein histopathology, Analytical Imaging Facilities, and Koch Institute for Microscopy, Histology and Flow Cytometry sorting core facilities for their services. Grant support provided by CA100324 (SG, YW), CA113395 (MHO), CA150344 (ETR), AECC9526-5267 (MHO, SG), Ludwig Fund postdoctoral fellowship (MB), GM58801 and funds from the Ludwig center at MIT (FBG), ICBP grant U54 CA112967 (FBG).

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Authors and Affiliations

  1. Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Evanthia T. Roussos, Sumanta Goswami, Yarong Wang & John S. Condeelis

  2. Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    John S. Condeelis

  3. David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Michele Balsamo & Frank B. Gertler

  4. Department of Biology, Yeshiva University, New York, NY, 10033, USA

    Sumanta Goswami & Robert Stobezki

  5. Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, 21287, USA

    Brian D. Robinson

  6. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, 10065, USA

    Joan G. Jones

  7. Department of Pathology, Montefiore Medical Center, Bronx, NY, 10467, USA

    Esther Adler & Maja H. Oktay

Authors
  1. Evanthia T. Roussos
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  2. Sumanta Goswami
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  3. Michele Balsamo
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  4. Yarong Wang
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  5. Robert Stobezki
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  6. Esther Adler
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  7. Brian D. Robinson
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  8. Joan G. Jones
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  9. Frank B. Gertler
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  10. John S. Condeelis
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Corresponding authors

Correspondence to Evanthia T. Roussos, John S. Condeelis or Maja H. Oktay.

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Roussos, E.T., Goswami, S., Balsamo, M. et al. Mena invasive (MenaINV) and Mena11a isoforms play distinct roles in breast cancer cell cohesion and association with TMEM. Clin Exp Metastasis 28, 515–527 (2011). https://doi.org/10.1007/s10585-011-9388-6

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  • DOI: https://doi.org/10.1007/s10585-011-9388-6

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