Role of Cuzd1 in mammary gland development and tumorigenesis

Anandan, Lavanya

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https://hdl.handle.net/2142/29561 Copy

Description

Title

Role of Cuzd1 in mammary gland development and tumorigenesis

Author(s)

Anandan, Lavanya

Issue Date

2012-02-01T00:55:28Z

Director of Research (if dissertation) or Advisor (if thesis)

Bagchi, Milan K.

Committee Member(s)

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

Department of Study

Molecular & Integrative Physl

Discipline

Molecular & Integrative Physi

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

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

Abstract

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.

Graduation Semester

2011-12

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Copyright and License Information

Copyright 2011 Lavanya Anandan

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