ErbB2/Neu overexpression, which occurs in 20-30% of breast cancers, is associated with resistance to traditional chemotherapeutic treatment, making it essential that we identify novel therapeutic targets. To investigate molecular mechanisms of ErbB2-induced tumorigenesis, we performed gene expression profiling on tissues from the MMTV-Neu mouse model. In this analysis, the transcriptional regulator LMO4 was upregulated 5 fold. LMO4 induces hyperplasia and tumors in mice. In addition, LMO4 is upregulated in 56% of primary human breast cancers. Interestingly, our microarray data analysis constitutes the first time intrinsic induction of LMO4 has been implicated in a mouse model of breast cancer, making this model ideal to study cancers where LMO4 is overexpressed. Further studies in our laboratory suggest that LMO4 is involved in regulation of cell cycle proteins. Prompted by these data, we hypothesize that LMO4 is necessary for ErbB2 tumor properties via a mechanism that involves regulation of the cell cycle. To address this hypothesis, we propose to identify the mechanisms underlying transcriptional control of the LMO4 promoter by ErbB2 and determine if LMO4 is necessary for maintaining ErbB2-mediated transformation. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA123642-02
Application #
7385007
Study Section
Special Emphasis Panel (ZRG1-IMM-L (29))
Program Officer
Bini, Alessandra M
Project Start
2006-09-21
Project End
2007-10-20
Budget Start
2007-09-21
Budget End
2007-10-20
Support Year
2
Fiscal Year
2007
Total Cost
$2,339
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
MontaƱez-Wiscovich, Marjorie E; Shelton, Melissa D; Seachrist, Darcie D et al. (2010) Aberrant expression of LMO4 induces centrosome amplification and mitotic spindle abnormalities in breast cancer cells. J Pathol 222:271-81
MontaƱez-Wiscovich, M E; Seachrist, D D; Landis, M D et al. (2009) LMO4 is an essential mediator of ErbB2/HER2/Neu-induced breast cancer cell cycle progression. Oncogene 28:3608-18