Role of human growth hormone regulated HOXA1 in mammary gland neoplastic progression

1 ROLE OF HUMAN GROWTH HORMONEREGULATED HOXA1 IN MAMMARY GLAND NEOPLASTIC PROGRESSION ZHANG XIN A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF MEDICINE NATIONAL UNIVERSITY OF SINGAPORE 2005 ROLE OF HUMAN GROWTH HORMONEREGULATED HOXA1 IN MAMMARY GLAND NEOPLASTIC PROGRESSION ZHANG XIN (B.S., Shangdong Medical University, Jinan, Shangdong, China) (M.S., Shangdong Medical University, Jinan, Shangdong, China) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF MEDICINE NATIONAL UNIVERSITY OF SINGAPORE 2005 Acknowledgement I would like to thank the following individuals for their support and help during the course of this experience Professor K O Lee and Associate Professor Peter Lobie, my supervisors, for their guidance, constant support and encouragement Also for their advice on my career and different aspects of life To all the members of the Endocrine and Signal Transduction labs, for the collaboration, interactions, advice and help To all the members in the Department of Medicine, particularly Associate Professor Benjamin Ong and Nancy, for being so helpful and kind My parents and my sister and my wife for their deeply love and being my strength Table of Contents Acknowledgements…………………………………………………………………… i Table of Contents……………………………………………………………………… ii Summary………………………………………………………………………………….v List of publications and presentations………………………………… ………… vii Abbreviations……………………………………………………………………….….viii Chapter Introduction……………………………………………………………… Chapter Literature review………………………………………………………… 2.1 Growth hormone (GH)……………………………………………………… 2.2 Growth hormone and mammary gland development and neoplasia………15 2.3 Autocrine GH and breast cancer…………………………………………… 20 2.4 Homeobox genes………………………………………………………………32 2.5 Homeodomain…………………………………………………………………36 2.6 Homeobox genes and development………………………………………… 38 2.7 Cellular effects and targets of homeobox genes…………………………… 44 2.8 Homeobox genes and human diseases……………………………………… 51 2.9 Homeobox genes and cancers………………………………………… ……54 2.10 Homeobox genes and mammary gland…………………………….……… 63 2.11 E-cadherin……………………………………………………… ……………76 2.12 E-cadherin directed signaling…………………………………….………… 82 Chapter Materials and methods………………………………………… ……….88 Chapter Results………………………………………………………….……… 113 4.1 Human GH-regulated HOXA1 is a human mammary epithelial oncogene…113 4.1.1 Autocrine hGH stimulation of mammary carcinoma cells increases HOXA1 mRNA, protein, and transcriptional activity……………………………… …………115 4.1.2 Forced expression of HOXA1 in human mammary carcinoma cells results in increased total cell number……………………………………………….…………….120 4.1.3 HOXA1 expression in human mammary carcinoma cells prevents apoptotic cell death in a Bcl-2 dependent manner…………………………………….………… 132 4.1.4 HOXA1 expression in mammary carcinoma cells protects against doxorubicin-induced apoptosis………………………………………………………….140 4.1.5 Forced expression of HOXA1 in human mammary carcinoma cells results in increased anchorage-independent growth in a Bcl-2-dependent manner………… 146 4.1.6 Forced expression of HOXA1 results in oncogenic transformation of immortalized human mammary epithelial cells in vitro………………………………152 4.1.7 Forced expression of HOXA1 results in oncogenic transformation of immortalized human mammary epithelial cells in vivo……………………………….163 4.2 E-cadherin-directed signaling upregulates HOXA1 through Rac1…… … 170 4.2.1 HOXA1 mRNA, protein, and transcriptional activity are increased in human mammary carcinoma cells at full confluence ……… ……… ……172 4.2.2 The increment in HOXA1 expression in human mammary carcinoma cells at full confluence is cell-cell adhesion dependent…………………….….…… 177 4.2.3 The increment in HOXA1 expression in human mammary carcinoma cells at full confluence is E-cadherin dependent…………………….……… …… 183 4.2.4 The increment in HOXA1 expression in human mammary carcinoma cells at full confluence is regulated by E-cadherin-activated signaling……… … 190 4.2.5 Rac1, but not PI-3 kinase, α-, β-, or γ-catenins is involved in the Ecadherin-activated increment in HOXA1 expression in human mammary carcinoma cells……………………………………….……………… … … 194 4.2.6 Increased HOXA1 expression by E-cadherin-activated signaling has increased anti-apoptotic effect in human mammary carcinoma cells…… 201 Chapter General discussion………………………………………………… …206 References…………………………………………………………………… ……….222 Summary Autocrine production of human growth hormone (hGH) by human mammary carcinoma cells may direct human mammary carcinoma cell behavior to impact on the final clinical prognosis One major mechanism by which GH affects cellular and somatic function is by regulating the level of specific mRNA species To investigate the regulation of homeobox gene HOXA1 by autocrine production of hGH in human mammary carcinoma cells (MCF-7), which was identified by previous researchers using cDNA miroarray analyses, the present study used an in vitro model of MCF-7 cells stably transfected with the wild-type hGH gene (MCF7-hGH) and a control stably transfected with a translationdeficient hGH gene (MCF7-MUT) The production of autocrine hGH increased HOXA1 mRNA, protein, and transcriptional activity in human mammary carcinoma cells Forced expression of HOXA1 in MCF-7 cells resulted in increased total cell number HOXA1 expression in MCF-7 cells prevented apoptotic cell death in a Bcl-2-dependent manner HOXA1 expression in MCF-7 cells also protected against doxorubicin-induced apoptosis Forced expression of HOXA1 in MCF-7 cells, in a Bcl-2-dependent manner, resulted in dramatic increase in anchorage-independent proliferation in suspension culture and colony formation in soft agar HOXA1 overexpression was sufficient to oncogenically transform spontaneously immortalized human mammary epithelial cells (MCF-10A) with resultant colony formation in soft agar When implanted into the mammary (axillary) fat pad of female severe combined immunodeficient mice (SCID mice), MCF-10A cells with overexpressed HOXA1 (MCF10A-HOXA1 cells) formed aggressive tumor in vivo Thus, human growth hormone-regulated HOXA1 is a human mammary epithelial oncogene HOXA1 was found to have increased expression in MCF-7 cells at full confluence This confluence-dependent expression of HOXA1 was abrogated by incubating the cell with EGTA which blocked the cell-cell adhesion or with an E-cadherin functional blocking antibody To distinguish the E-cadherin-dependent regulation from the E-cadherinactivated signaling regulation of HOXA1 expression, a functional E-cadherin ligand (hE/Fc) was utilized and this confluence-dependent expression of HOXA1 was confirmed to be direct downstream consequence of E-cadherin ligation Furthermore, E-cadherin increased HOXA1 at full confluence through Rac1 Increased HOXA1 expression at full confluence had increased anti-apoptotic effect in human mammary carcinoma cells These results indicated that a cross link may exist between E-cadherin and HOXA1 signaling pathways and that direct E-cadherin signaling may have anti-apoptotic effect List of publications and presentations I Overexpression of human growth hormone-regulated HOXA1 results in oncogenic transformation of human mammary epithelial cells Zhang X, Zhu T, Lee KO, Lobie PE (2002) Abstract presented at Endocrine Society meeting and awarded a 2002 Endocrine Society Travel Award II Human growth hormone-regulated HOXA1 is a human mammary epithelial oncogene Zhang X, Zhu T, Chen Y, Mertani HC, Lee KO, Lobie PE (2003) J Biol Chem 2003 Feb 28; 278(9):7580-90 III Oncogenic transformation of human mammary epithelial cells by human autocrine growth hormone Zhu T, Starlin-Emerald B, Zhang X, Lee KO, Gluckman PD, Mertani HC, ,Lobie PE (2005) Cancer Res 2005 Jan 1, 65(1):317-24 IV E-cadherin-directed signaling upregulates HOXA1 through Rac1 Zhang X, Chen Y, Lee KO, Lobie PE (manuscript in preparation) 10 Abbreviations ATP adenosine triphosphate bp base pair β-gal beta-galactosidase BSA bovine serum 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41(leucine/asparagine), 46(isoleucine/valine), 56(lysine/arginine),