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PMID: 15123840 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 17 ·2004-04-27 ·Pages 6478-83

Coletta RD, Christensen K, Reichenberger KJ, Lamb J, Micomonaco D, Huang L, Wolf DM, Müller-Tidow C, Golub TR, Kawakami K, Ford HL

Abstract

Homeobox genes constitute a large family of transcription factors that are essential during normal development and are often dysregulated in cancer. However, the molecular mechanisms by which homeobox genes influence cancer remain largely unknown. Here we show that the tissue-restricted cyclin A1 is a transcriptional target of the Six1 homeoprotein. Both genes are expressed in the embryonic but not the terminally differentiated mammary gland, and Six1-knockout mice show a dramatic reduction of cyclin A1 in the embryonic mammary gland. In addition, both genes are reexpressed in breast cancers. Six1 overexpression increases cyclin A1 mRNA levels and activity, cell proliferation, and tumor volume, whereas Six1 down-regulation decreases cyclin A1 mRNA levels and proliferation. Overexpression of Six1 in wild-type mouse embryonic fibroblasts, but not in knockout variants lacking the cyclin A1 gene, induces cell proliferation. Furthermore, inhibition of cyclin A1 in Six1-overexpressing mammary carcinoma cells decreases proliferation. Together these results demonstrate that cyclin A1 is required for the proliferative effect of Six1. We conclude that Six1 overexpression reinstates an embryonic pathway of proliferation in breast cancer by up-regulating cyclin A1.

MeSH Terms
Animals Blotting, Western Breast Neoplasms/genetics,metabolism,pathology Cell Division Cell Line Cell Transformation, Neoplastic Cyclin A/genetics,metabolism Cyclin A1 Gene Expression Regulation, Neoplastic Homeodomain Proteins/genetics,physiology Humans Mice Mice, Nude Neoplasm Transplantation Precipitin Tests Reverse Transcriptase Polymerase Chain Reaction
Chemicals
CCNA1 protein, human Ccna1 protein, mouse Cyclin A Cyclin A1 Homeodomain Proteins SIX1 protein, human Six1 protein, mouse
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Coletta Ricardo D
Department of Obstetrics and Gynecology, University Colorado Health Sciences Center, Denver, CO 80262, USA.
Christensen Kimberly
Reichenberger Kelly J
Lamb Justin
Micomonaco Damian
Huang Lili
Wolf Douglas M
Müller-Tidow Carsten
Golub Todd R
Kawakami Kiyoshi
Ford Heide L
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0401139101
Published
2004-04-27
Epub
2004-00-26
Pages
6478-83
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC404070
Subset
IM
Grants
NCI NIH HHS · R01 CA095277 · United States
NCI NIH HHS · 1R01CA095277-01 · United States
External Links
PubMed source DOI: 10.1073/pnas.0401139101 PMC Full Text View journal details
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