The WNT-5a derived peptide, Foxy-5, possesses dual properties that impair progression of ERα negative breast cancer

Abstract

Despite improvements in detection and treatment, breast cancer remains the most common female cancer worldwide, and metastatic associated mortality is a significant public health issue. Patients with tumors negative for estrogen receptor (ERalpha), have a particularly poor prognosis, partly due to their inability to respond to current endocrine treaments. Expression of Wnt-5a has been associated with prolonged recurrence free survivial in clinical material, and Wnt-5a also inhibits migration and invasion of breast cancer cell lines. Loss of Wnt-5a is associated with loss of ERalpha in clinical breast cancer material, and Wnt-5a signaling upregulates ERalpha in ERalpha negative breast cancer cell lines. A Wnt-5a derived hexapeptide, Foxy-5, has been developed and like Wnt-5a, increases adhesion and inhibits migration of breast cancer cells. Furthermore, Foxy-5 significantly reduced liver and lung metastases in a murine ERalpha negative breast cancer model. Foxy-5 also upregulated ERalpha in this in vivo model and most significantly, in vitro rendered cells responsive to the selective estrogen receptor modulator, Tamoxifen. Together these studies suggest that Foxy-5 may be a potential new supplementary treatment for ERalpha negative breast cancer patients, as it addresses two of the most important aspects of cancer related mortality -- non response to endocrine therapy and metastasis.

Gene Expression Profiling Reveals New Aspects of PIK3CA Mutation in ERalpha-Positive Breast Cancer: Major Implication of the Wnt Signaling Pathway

“…Crosstalk of complex pathways belonging to Wnt signaling has been observed leading to, when altered, disparate effects in different tumor types [22]-[24]. We observed over-expression of four major genes involved in the Wnt pathway, namely WNT5A , TCF7L2 , MSX2 and TNFRSF11B .…”

“…WNT5A encodes a major Wnt ligand affecting tumor cell motility and metastasis, but its role in breast cancer is controversial [23]. The emerging view is that, in breast cancer, WNT5A has a suppressive effect, inhibiting migration and invasion of breast cancer cell lines [24]. Moreover, WNT5A over-expression observed in invasive breast tumors has been associated with a favorable outcome [24].…”

Prognostic role of PIK3CA mutations and their association with hormone receptor expression in breast cancer: a meta-analysis

“…Cizkova showed that the Wnt pathway was dysregulated and WNT5A was overexpressed in ER+ BCa patients with PIK3CA mutations41. Interestingly, WNT5A expression has been associated with favorable outcomes in patients with invasive breast tumors42. Third, PIK3CA , like many other oncogenes, may induce senescence, resulting in a less aggressive phenotype after cell transformation4344.…”

International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors

“…This peptide, named FOXY-5 (see Fig. 8), indeed turned out to impair the progression of estrogen receptor ␣-deficient breast cancer: FOXY-5 increases cell adhesion, thereby reducing migration of breast cancer cells, and induces expression of estrogen receptor ␣, rendering the cells sensitive to tamoxifen (Ford et al, 2009). The same research group also developed a t-butyloxycarbonylmodified WNT-5A-derived hexapeptide (t-butyloxycarbonyl-Met-Asp-Gly-Cys-Glu-Leu), named BOX-5 (see Fig.…”