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Breast Cancer Research and Treatment

, Volume 137, Issue 3, pp 709–719 | Cite as

Elevated expression of podocalyxin is associated with lymphatic invasion, basal-like phenotype, and clinical outcome in axillary lymph node-negative breast cancer

  • Catherine L. Forse
  • Yildiz E. Yilmaz
  • Dushanthi Pinnaduwage
  • Frances P. O’Malley
  • Anna Marie Mulligan
  • Shelley B. Bull
  • Irene L. AndrulisEmail author
Preclinical Study

Abstract

Lymphatic invasion (LVI) is associated with disease recurrence in axillary node-negative (ANN) breast cancer. Using gene expression profiling of 105 ANN tumors, we found that podocalyxin (PODXL) was more highly expressed in tumors with LVI (LVI+) than in those without LVI (LVI−). Differences in PODXL expression were validated using real-time polymerase chain reaction as well as by immunohistochemistry in an independent set of 652 tumors on tissue microarrays. Disease-free survival (DFS) analyses were conducted for association of high PODXL protein expression with risk of distant recurrence overall and within breast cancer subtypes using both Cox and cure-rate models. High PODXL expression was associated with poor prognosis features including large tumor size, high histological grade, estrogen and progesterone receptor negativity, and with clinical alterations characteristic of the basal-like breast cancer phenotype. Surprisingly, despite having other poor prognosis characteristics, women with high PODXL expressing tumors had better long-term DFS in multivariate analysis with traditional clinicopathologic factors including LVI and HER2 status (P = 0.001). PODXL has the potential to be a useful biomarker for identifying good prognosis patients in characteristically poor prognosis breast cancer groups and may impact treatment of women with this disease.

Keywords

Podocalyxin Lymphatic invasion Breast cancer Cure-rate model 

Abbreviations

ANN

Axillary node-negative

CK5

Cytokeratin 5

DFS

Disease-free survival

EGFR

Epidermal growth factor receptor

ER

Estrogen receptor

GEA

Gene expression array

HER2

Human epidermal growth factor receptor 2

HR

Hazard ratio

IHC

Immunohistochemistry

K–M

Kaplan–Meier

LVI

Lymphatic invasion

OR

Odds ratio

PH

Proportional hazards

p53

Protein 53

PODXL

Podocalyxin

PgR

Progesterone receptor

RT-PCR

Real-time polymerase chain reaction

TMA

Tissue microarray

Notes

Acknowledgments

This study has been supported by a grant from the Canadian Institutes of Health Research and with funds provided by the Terry Fox Run (ILA, SBB, FO’M), by a Senior Investigator award from the Canadian Institutes of Health Research (SBB), and by project funds from the MITACS Network of Centres of Excellence in Mathematical Sciences (SBB). YEY is supported by MITACS Industrial Fellowship and a CIHR Fellow in Genetic Epidemiology and Statistical Genetics with CIHR STAGE (Strategic Training for Advanced Genetic Epidemiology). The authors thank the study participants and gratefully acknowledge the technical assistance of Lucine Bosnoyan-Collins and Suzanne Tjan and the contributions of the Toronto Breast Cancer Group to this work. We also thank Candemir Cigsar for statistical insights.

Conflict of interest

The authors declare they have no conflicts of interest.

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Catherine L. Forse
    • 1
    • 3
  • Yildiz E. Yilmaz
    • 2
    • 5
  • Dushanthi Pinnaduwage
    • 2
  • Frances P. O’Malley
    • 6
    • 4
  • Anna Marie Mulligan
    • 4
    • 8
  • Shelley B. Bull
    • 2
    • 5
  • Irene L. Andrulis
    • 1
    • 3
    • 7
    • 4
    Email author
  1. 1.Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  2. 2.Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  3. 3.Department of Molecular GeneticsUniversity of TorontoTorontoCanada
  4. 4.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  5. 5.Dalla Lana School of Public HealthUniversity of TorontoTorontoCanada
  6. 6.Department of Laboratory Medicine and the Keenan Research Centre of the Li Ka Shing Knowledge InstituteSt. Michael’s HospitalTorontoCanada
  7. 7.Department of Pathology and Laboratory MedicineMount Sinai HospitalTorontoCanada
  8. 8.Department of PathologyUniversity Health NetworkTorontoCanada

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