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Regulation of Stromal Versican Expression by Breast Cancer Cells and Importance to Relapse-free Survival in Patients with Node-negative Primary Breast Cancer¹

Flinders Cancer Centre, Departments of Surgery [C. R., J. H. B., S. S., A. J. S., K. M., D. J. H.], Anatomical Pathology [W. A. R.], and Haematology and Genetic Pathology [R. S.], Flinders University Medical Research Institute and Flinders Medical Centre, Adelaide, South Australia, 5042, Australia, and Division of Life Sciences, Cell and Molecular Biology, University of Texas, San Antonio, Texas 78249 [R. G. L.]

Purpose: Determination of meaningful prognostic indicesremains a high priority for women diagnosed with node-negative primary breast cancer. Currently, 30% of these women relapse, and there is no reliable means of predicting this group of patients. This study investigates whether the level of expression of versican, an anticell adhesive proteoglycan, in the peritumoral stromal tissue of women with node-negative, primary breast cancer predicts relapse-free survival. This study also examines whether breast cancer cells regulate the secretion of versican by mammary fibroblasts.

Experimental Design: Immunoreactive versican was measured in breast cancer tissue sections of 58 node-negative patients by video image analysis. Primary isolates of mammary fibroblasts were cultured in medium conditioned by the breast cancer cell lines ZR-75-1, MCF-7, BT-20, and MB231. Changes in versican secretion were measured by immunoblotting and enhanced chemiluminescence.

Results: Cox analyses indicated that peritumoral versican level was the sole predictor of relapse-free survival. The relapse rate in patients with low versican levels was lower than in patients with high versican levels (Kaplan-Meier: 83% relapse free at 5 years for versican mean integrated absorbance <14 versus 33% for 14, P = 0.0006). Accumulation of versican in medium of mammary fibroblasts was increased after culture in conditioned medium from breast cancer cell lines.

Conclusions: Relapse in women with node-negative breast cancer is related to the level of versican deposited in peritumoral stroma by mammary fibroblasts. Versican secretion appears to be regulated by breast cancer cell mediators. Neoplastic remodeling of extracellular matrix through increased versican deposition may facilitate local invasion and metastasis.

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