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Mammary tumor regression elicited by Wnt signaling inhibitor requires IGFBP5
Bob Y Liu1, Irina Soloviev, XiaoDong Huang
1Department of Cancer Targets, Genentech Inc., South San Francisco, California 94080, USA.
Abstract:
Wnt ligand-driven tumor growth is inhibited by the soluble Wnt inhibitor Fzd8CRD, but the mechanism through which this effect is mediated is unknown. In the MMTV-Wnt1 mouse model, regression of mammary tumors by Fzd8CRD treatment coincides with an acute and strong induction of insulin-like growth factor (IGF)-binding protein IGFBP5, an antagonist of IGF signaling that mediates involution of mammary gland in females after offspring are weaned. In this study, we show that repression of this IGF inhibitory pathway is crucial for Wnt-driven growth of mammary tumors. We found that IGFBP5 regulation was mediated by the β-catenin-dependent Wnt pathway. Wnt, in addition to IGF ligands, facilitated tumor growth by paracrine communication among tumor cells. In addition, Fzd8CRD caused precocious induction of IGFBP5 in normal mammary glands undergoing involution, implying an acceleration of the involution process by inhibition of Wnt signaling. The molecular and phenotypic parallel between tumor regression and mammary gland involution suggests that Wnt-driven mammary tumors use the same growth mechanism as proliferating normal mammary glands.
Insights
The soluble Wnt inhibitor Fzd8CRD halts Wnt-driven tumor growth by inducing insulin-like growth factor-binding protein 5 (IGFBP5), mimicking mammary gland involution. This reveals a shared growth mechanism between Wnt-driven tumors and normal mammary glands.
Area of Science:
- Oncology
- Developmental Biology
- Endocrinology
Background:
- Wnt signaling pathways are critical drivers of mammary tumor growth.
- Soluble Wnt inhibitors, such as Fzd8CRD, can impede tumor progression.
- The precise mechanisms by which Wnt inhibitors affect tumor growth are not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which Fzd8CRD inhibits Wnt ligand-driven mammary tumor growth.
- To investigate the role of insulin-like growth factor-binding protein 5 (IGFBP5) in Wnt-driven mammary tumorigenesis.
- To explore the parallels between mammary tumor regression and mammary gland involution.
Main Methods:
- Utilized the MMTV-Wnt1 mouse model for mammary tumor studies.
- Administered Fzd8CRD to assess tumor regression and molecular changes.
- Analyzed the expression and regulation of IGFBP5.
- Investigated Wnt pathway activation and its downstream effects.
Main Results:
- Fzd8CRD treatment led to mammary tumor regression, coinciding with a significant induction of IGFBP5.
- IGFBP5 induction was mediated by the β-catenin-dependent Wnt pathway.
- Wnt signaling, alongside IGF ligands, promoted tumor growth via paracrine communication.
- Fzd8CRD induced precocious IGFBP5 expression in normal mammary glands, accelerating involution.
Conclusions:
- Repression of the IGF inhibitory pathway, mediated by IGFBP5, is essential for Wnt-driven mammary tumor growth.
- Wnt-driven mammary tumors share growth mechanisms with proliferating normal mammary glands, utilizing pathways that can be targeted to induce involution-like processes for therapeutic benefit.
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