The development of bone metastases is one of the most debilitating complications of advanced breast cancer. Patients suffer from severe pain, spontaneous fractures and possible spinal cord compression caused by development of osteolytic lesions. We don't understand how breast cancer cells develop the ability to metastasize and proliferate in bone. As a consequence, therapeutic options at this advanced stage of breast cancer are extremely limited. Breast cancer bone metastatic cells undergo striking changes, expressing genes involved in bone development such as OPN, MMPs, VEGF, all known markers of tumor growth, invasion and metastasis. Importantly, these genes are controlled by the master regulator of bone formation RUNX2, and RUNX2 becomes overexpressed in breast cancer metastatic cells. We identified that the WWOX tumor suppressor protein physically interacts with and represses RUNX2 transcriptional activity. We hypothesize that loss of WWOX expression (a common event in breast cancer) is key for the progression of breast cancer cells towards development of a bone metastatic phenotype. Our current research suggests that loss of WWOX in breast cancer cells leads to unrestrained RUNX2 activity, Osteopontin overexpression and these maybe key determinants for metastasis development. We expect aborting development of bone metastases by restoring function of the WWOX-RUNX2 axis. We have also created a conditional Wwox KO mouse that will allow in vivo study of effects in mammary gland growth, tumor development and metastasis. Therefore we will pursue the following Specific Aims:
Aim 1 : We will A. determine whether WWOX depletion alters the phenotype of normal mammary epithelial and non-metastatic breast cancer cells and B. determine the effects of restoring WWOX expression in metastatic breast cancer cells.
Aim 2 : A. To determine whether WWOX restoration suppresses spontaneous bone metastasis and osteolytic bone disease in breast cancer metastatic cells. B. To determine if WWOX depletion induces a metastatic and osteolytic phenotype in non-metastatic breast cancer cells. C. To determine whether WWOX influences the ability of breast cancer cells to crosstalk with the bone microenvironment by affecting osteogenic differentiation.
Aim 3 : To determine whether the integrity of the WWOX-RUNX2 physical interaction is relevant for impeding bone metastases and associated osteolytic disease.
Aim 4 : To determine whether targeted Wwox ablation in the mammary gland leads to enhanced mammary tumorigenesis and increases metastasis. The proposed studies will provide novel information on the mechanistic basis of bone metastasis development and identify potential novel targets for therapeutic intervention.

Public Health Relevance

We do not understand how breast cancer cells develop the ability to metastasize and proliferate in bone;therapeutic options at this advanced stage of breast cancer are extremely limited. We hypothesized that loss of expression of the tumor suppressor WWOX in breast cancer cells leads to unrestrained activity of the RUNX2 transcription factor and that this maybe a key determinant of metastasis development. The proposed studies will test this hypothesis, provide novel information on the mechanistic basis of bone metastasis development and identify potential novel targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102444-08
Application #
8265684
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Woodhouse, Elizabeth
Project Start
2003-09-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$333,032
Indirect Cost
$122,252
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Iatan, Iulia; Choi, Hong Y; Ruel, Isabelle et al. (2014) The WWOX gene modulates high-density lipoprotein and lipid metabolism. Circ Cardiovasc Genet 7:491-504
Aldaz, C Marcelo; Ferguson, Brent W; Abba, Martin C (2014) WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies. Biochim Biophys Acta 1846:188-200
Mallaret, Martial; Synofzik, Matthis; Lee, Jaeho et al. (2014) The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation. Brain 137:411-9
Ludes-Meyers, John H; Kil, Hyunsuk; Parker-Thornburg, Jan et al. (2009) Generation and characterization of mice carrying a conditional allele of the Wwox tumor suppressor gene. PLoS One 4:e7775
Pimenta, Flavio Juliano; Cordeiro, Gabriela Tavares; Pimenta, Luiz Gustavo Garcia Santos et al. (2008) Molecular alterations in the tumor suppressor gene WWOX in oral leukoplakias. Oral Oncol 44:753-8
Ramos, D; Abba, M; Lopez-Guerrero, J A et al. (2008) Low levels of WWOX protein immunoexpression correlate with tumour grade and a less favourable outcome in patients with urinary bladder tumours. Histopathology 52:831-9
Dias, Eduardo P; Pimenta, Flavio J; Sarquis, Marta S et al. (2007) Association between decreased WWOX protein expression and thyroid cancer development. Thyroid 17:1055-9
Ludes-Meyers, John H; Kil, Hyunsuk; Nunez, Maria I et al. (2007) WWOX hypomorphic mice display a higher incidence of B-cell lymphomas and develop testicular atrophy. Genes Chromosomes Cancer 46:1129-36
Ramos, D; Aldaz, C M (2006) WWOX, a chromosomal fragile site gene and its role in cancer. Adv Exp Med Biol 587:149-59
Pimenta, Flavio J; Gomes, Dawidson A; Perdigao, Paolla F et al. (2006) Characterization of the tumor suppressor gene WWOX in primary human oral squamous cell carcinomas. Int J Cancer 118:1154-8

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