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Poor Outcome in Estrogen Receptor–Positive Breast Cancers Predicted by Loss of Plexin B1

Authors' Affiliations: Departments of ¹ Obstetrics and Gynecology, ² Pathology, and ³ Computer Science and Mathematics, Johann Wolfgang Goethe University, Frankfurt, Germany; ⁴ Bayer Healthcare AG, Leverkusen, Germany; ⁵ German Breast Group, Neu-Isenburg, Germany; and ⁶ Department of Pathology, Heinrich Heine-University, Duesseldorf, Germany

Requests for reprints: Thomas Karn, Department of Obstetrics and Gynecology, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60596 Frankfurt, Germany. Phone: 49-69-6301-4120; E-mail: t.karn{at}em.uni-frankfurt.de.

Purpose: A common characteristic of mammary carcinomas is an inverse relationship between the estrogen receptor (ER) status and the proliferative activity of the tumor. Yet, a subset of ER-positive breast cancers is characterized by a high proliferation, suggesting malfunctions in ER responsiveness that influence the biological and therapeutic behavior of tumor cells. The expression of several ER-dependent genes seems to be dysregulated among those "uncoupled" tumors. One of those genes is plexin B1, a cell-surface receptor for the semaphorin Sema4D (CD 100). However, the biological role of plexin B1 in breast cancer is largely unknown.

Experimental Design: Expression data of plexin B1 were obtained from Affymetrix microarray analysis of n = 119 breast cancer specimens. Validation was done by quantitative real-time PCR and protein expression was evaluated by immunohistochemistry. Expression data were compared with clinical characteristics as well as follow-up data of the disease.

Results: Low plexin B1 expression levels characterize a more aggressive tumor phenotype. The expression of plexin B1 is strongly correlated with the ER status. However, even among ER-positive tumors, loss of plexin B1 is associated with an impaired prognosis of breast cancer patients in both univariate (all patients, P = 0.0062; ER positive, P = 0.0107) and multivariate analyses (all patients, P = 0.032; ER positive, P = 0.022). Immunohistochemistry reveals that the tumor cells themselves and not the endothelial cells are the major source of plexin B1 expression in the tumor.

Conclusion: Plexin B1 acts not only as a new important prognostic but should also represent a predictive marker indicating an endocrine resistance. These data give a new insight in markers that could be involved in endocrine dysregulation of breast cancer.