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J. Biol. Chem., Vol. 281, Issue 10, 6471-6481, March 10, 2006

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HOXA1 Is Required for E-cadherin-dependent Anchorage-independent Survival of Human Mammary Carcinoma Cells^*

Xin Zhang, B. Starling Emerald, Svetlana Mukhina^¶, Kumarasamypet M. Mohankumar, Astrid Kraemer^||, Alpha S. Yap^||, Peter D. Gluckman, Kok-Onn Lee, and Peter E. Lobie¹

From the Department of Medicine and ^¶Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Dr., Singapore 117609, Republic of Singapore, the ^||Division of Molecular Cell Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia 4072, Queensland, Australia, and The Liggins Institute and National Research Centre for Growth and Development, University of Auckland, 2-6 Park Avenue, Private Bag 92019, Auckland 1001, New Zealand

Forced expression of HOXA1 is sufficient to stimulate oncogenic transformation of immortalized human mammary epithelial cells and subsequent tumor formation. We report here that the expression and transcriptional activity of HOXA1 are increased in mammary carcinoma cells at full confluence. This confluence-dependent expression of HOXA1 was abrogated by incubation of cells with EGTA to produce loss of intercellular contact and rescued by extracellular addition of Ca²⁺. Increased HOXA1 expression at full confluence was prevented by an E-cadherin function-blocking antibody and attachment of non-confluent cells to a substrate by homophilic ligation of E-cadherin increased HOXA1 expression. E-cadherin-directed signaling increased HOXA1 expression through Rac1. Increased HOXA1 expression consequent to E-cadherin-activated signaling decreased apoptotic cell death and was required for E-cadherin-dependent anchorage-independent proliferation of human mammary carcinoma cells. HOXA1 is therefore a downstream effector of E-cadherin-directed signaling required for anchorage-independent proliferation of mammary carcinoma cells.

Received for publication, November 28, 2005

^* This work was supported by grants from The National Research Centre for Growth and Development, New Zealand (Theme 2), The Marsden Fund, Royal Society of New Zealand, The Queensland Cancer Fund, Wellcome Trust (UK), and the Agency of Science, Technology and Research of Singapore. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 64-9-373-7599 (ext. 82125); Fax: 64-9-373-7497; E-mail: p.lobie{at}auckland.ac.nz.

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