The Prognostic Significance of Wnt-5a Expression in Primary Breast Cancer Is Extended to Premenopausal Women

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From: PLoS ONE(Vol. 8, Issue 8)
Publisher: Public Library of Science
Document Type: Article
Length: 5,766 words
Lexile Measure: 1470L

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Author(s): Janna Sand-Dejmek 1,2,*, Roy Ehrnström 3, Pontus Berglund 1, Tommy Andersson 1, Lisa Ryden 4


Breast cancer is a heterogenous disease. The heterogeneity of the disease affects not only the prognosis but also the choice of treatment [1]. One very important factor in this context is the menopausal status of the patient. Breast cancer in premenopausal women is generally more aggressive and has a poor prognosis [1]. As a reflection of the difference between breast cancer in women with varying menopausal status, breast cancer in premenopausal females are more often estrogen receptor negative (ER-) although >50% of premenopausal breast cancer are ER+ [2]. Furthermore, premenopausal breast cancers usually have higher proliferation indices than tumors in postmenopausal women [3]. Consequently, studies on the prognostic value of new biomarkers have to properly address this heterogeneous property of breast cancer.

Wnt proteins belong to a family of secreted proteins involved in a wide range of cellular processes. Wnt signaling can be broadly divided into two categories; the canonical, ß-catenin-dependent pathway and the non-canonical ß-catenin-independent pathway. Wnt signaling is initiated by binding of a Wnt ligand to its receptor(s). Canonical Wnt signaling results in stabilization of the key transcription factor ß-catenin, leading to its translocation into the nucleus where it drives the expression of target genes such as cyclin D1 and c-MYC [4]. Wnt-5a is a non-canonical Wnt ligand that is ubiquitously expressed in normal tissues [5]. In cancer, Wnt-5a is often dysregulated and the protein has been implicated both in tumor suppressive as well as in tumor promoting activities [6]. In good agreement with these findings, Wnt-5a has been recognized both as a marker of favorable and of poor outcome in primary cancers. We, and others, have previously shown that loss or low expression of Wnt-5a in the primary tumor has an unfavorable prognostic value in breast, prostate and colon cancer [7], [8], [9], [10]. Loss or reduced Wnt-5a expression has also been reported in liver metastases from patients with colorectal cancer [11]. In primary hepatocellular carcinoma, neuroblastoma, lymphoma and thyroid cancer, loss of or reduced Wnt-5a expression has also been associated with an adverse outcome [6], [12]. On the other hand, a tumor promoting function has been strongly documented for Wnt-5a in melanoma and in melanoma elevated Wnt-5a expression has also been associated with poor prognosis [13], [14]. Similar results were also reported for the role and prognostic properties of Wnt-5a in gastric cancer [15]. Collectively, these findings underscore the complex functional and prognostic roles of Wnt-5a in cancer.

In experimental studies, we found that reconstitution of Wnt-5a signaling decreased the migratory capacity and invasiveness of cultured breast cancer cells and that administration of a Wnt-5a-mimicking peptide significantly reduced breast cancer metastases in a mouse model [16], [17]. Recently these findings have been confirmed and in addition it was shown that when 4T1 breast cancer cells were transfected to express Wnt-5a their injection into the tail vein of Balb/c mice resulted in significantly less lung metastases as compared to control...

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Gale Document Number: GALE|A478172203