This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, C. Articles by Schmidt, E. V. Search for Related Content PubMed PubMed Citation Articles by Yang, C. Articles by Schmidt, E. V.

Identification of Cyclin D1– and Estrogen-Regulated Genes Contributing to Breast Carcinogenesis and Progression

¹ Massachusetts General Hospital Cancer Research Center; ² Department of Family Medicine, Boston University Medical Center; ³ Molecular Biology and ⁴ The Pediatric Service, Massachusetts General Hospital, Boston, Massachusetts; ⁵ Department of Radiotherapy, Royal Marsden Hospital, London, United Kingdom; and ⁶ Molecular Pathology Unit, Massachusetts General Hospital-East, Charlestown, Massachusetts

Requests for reprints: Emmett V. Schmidt, Massachusetts General Hospital Cancer Research Center, Massachusetts General Hospital Cancer Center-Harvard University, 55 Fruit Street, GRJ 904, Boston, MA 02114. Phone: 617-726-5707; Fax: 617-726-4466; E-mail: schmidt{at}helix.mgh.harvard.edu.

Tumors can become lethal when they progress from preinvasive lesions to invasive carcinomas. Here, we identify candidate tumor progression genes using gene array analysis of preinvasive and invasive tumors from mice, which were then evaluated in human cancers. Immediate early response protein IEX-1, small stress protein 1 (HSPB8), and tumor necrosis factor-associated factor–interacting protein mRNAs displayed higher expression levels in invasive lesions than in preinvasive lesions using samples obtained by laser capture microdissection (LCM) from transgenic erbB2, ras, and cyclin D1 mice. LCM-isolated tissues from patient-matched normal, ductal carcinoma in situ, and invasive ductal carcinoma revealed similar increased expression in invasive human cancers compared with preinvasive and normal samples. These genes induced anchorage independence, increased cell proliferation, and protected against apoptosis, singly or in collaboration with erbB2. Surprisingly, they were all up-regulated by 17ß-estradiol and cyclin D1, and cyclin D1 overexpression increased p300/CBP binding to their promoters, supporting the model that cyclin D1-estrogen receptor (ER) coactivator interactions may be important to its role in ER-positive breast cancer. Additionally, an irreversible dual kinase inhibitor of ErbB signaling inhibited expression of the same genes. The up-regulation of genes contributing to increased invasiveness of ER-positive cancers offers a novel explanation for the contribution of cyclin D1 to a worse prognosis in ER-positive cancers. As targets of estrogen, cyclin D1, and erbB2 signaling, these candidates offer insights into the nature of the second events involved in breast cancer progression, regulatory events contributing to invasion, and potential targets of combined inhibition of hormone and growth factor signaling pathways. (Cancer Res 2006; 66(24): 11649-58)

This article has been cited by other articles:

				Z. Madak-Erdogan, K. J. Kieser, S. H. Kim, B. Komm, J. A. Katzenellenbogen, and B. S. Katzenellenbogen Nuclear and Extranuclear Pathway Inputs in the Regulation of Global Gene Expression by Estrogen Receptors Mol. Endocrinol., September 1, 2008; 22(9): 2116 - 2127. [Abstract] [Full Text] [PDF]

				T. Sasada, K. Azuma, T. Hirai, H. Hashida, M. Kanai, T. Yanagawa, and A. Takabayashi Prognostic Significance of the Immediate Early Response Gene X-1 (IEX-1) Expression in Pancreatic Cancer Ann. Surg. Oncol., February 1, 2008; 15(2): 609 - 617. [Abstract] [Full Text] [PDF]

				S. Trent, C. Yang, C. Li, M. Lynch, and E. V. Schmidt Heat Shock Protein B8, a Cyclin-Dependent Kinase Independent Cyclin D1 Target Gene, Contributes to Its Effects on Radiation Sensitivity Cancer Res., November 15, 2007; 67(22): 10774 - 10781. [Abstract] [Full Text] [PDF]