Role of Cuzd1 in mammary gland development and tumorigenesis

The mechanisms by which the pathways regulated by the steroid hormones and the epidermal growth factor (EGF) family control mammary development are unclear. We have identified the CUB and zona pellucida-like domain containing protein-1 (CUZD1) as a target of estrogen regulation in the mouse mammary epithelium. Mice lacking Cuzd1 exhibited a striking impairment in steroid-induced proliferation of mammary ductal and alveolar epithelium. Our study revealed that Cuzd1 controls the production of a subset of EGF family growth factors, neuregulin-1, epigen and epiregulin, which act via the ERBB receptors on the mammary epithelial cells. Interestingly, exposure of these cells to the EGF-like growth factors stimulated CUZD1 expression, triggered its nuclear translocation, and promoted CUZD1-dependent mitogenic activity. We postulated that a regulatory loop, involving the EGF-like growth factors and CUZD1, contributes to mammary epithelial proliferation, and that dysregulation of CUZD1 expression may induce tumorigenesis. Indeed, orthotopic injection of mammary epithelial cells overexpressing Cuzd1 into mammary glands of mice led to the development of malignant breast tumors, which metastasized to other tissues. Analysis of Cuzd1 expression in primary human breast tumors revealed a significantly elevated expression of this gene in tumors displaying a high level of estrogen receptor alpha (ESR1) and ERBB signaling. Collectively, these findings suggested that uncontrolled expression of CUZD1, which is a unique integrator of steroid- and EGF family-induced growth pathways in normal mammary epithelium, leads to breast tumorigenesis. Designing therapeutics that target CUZD1 may offer a novel intervention strategy against breast tumor progression, invasion and metastasis.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Molecular & Integrative Physi

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2012

Author dc:creator

• Anandan, Lavanya

Contributors dc:contributor

• Bagchi, Milan K.
• Bagchi, Indrani C.
• Katzenellenbogen, Benita S.
• Kemper, Byron W.
• Raetzman, Lori T.

• CUB and zona pellucida-like domain containing protein-1 (CUZD1)
• mammary gland
• proliferation
• tumorigenesis
• breast cancer

Statement dc:rights

• Copyright 2011 Lavanya Anandan

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/29561

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/29561