Abstract
Abstract : Breast cancer commonly metastasizes to the skeleton in patients with advanced disease to cause either bone destruction or new bone formation. Since patients with breast cancer may survive several years with their bone metastases, it is important to understand the pathophysiology of this process in order to improve therapy and prevention. The proposed work seeks to investigate tumor cell-bone interactions in breast cancer metastases to bone with specific attention to the role of: (1) estrogen receptor-alpha (ER-alpha in mediating tumor production of bone-active factors to cause osteolytic and osteoblastic metastases using a mouse model of bone metastases, and (2) bone-derived transforming growth factor Beta (TGFBeta) in modulating the effects of ER-alpha on tumor cell growth in bone. Defining the mechanisms responsible for breast cancer metastases to bone will provide insight into future therapy and prevention. The following hypotheses will be tested: (1) Estrogen stimulates breast cancer cell production of factors which disrupt normal bone remodeling to result in osteolytic or osteoblastic metastases. (2) Estrogen stimulates PTHrP production by TGFBeta-responsive breast cancer cells to result in osteolytic metastases. TGFBeta enhances ER-alpha-mediated transcriptional activity in breast cancer cells to stimulate growth. (3) Estrogen stimulates production of osteoblastic factors, such as ET-1, by breast cancer cells,which are TGFBeta unresponsive. Restoration of TGFBete responsiveness should result in PTHrP production and osteolytic metastases. Three specific aims were proposed to test the hypotheses and we report here the progress for Specific aim 1 in year 1 of this Academic Award: (1) To determine the role of ER-alpha in osteolytic or osteoblastic breast cancer metastases to bone using an in vivo model. Stable MDA-MB-231 cell lines were constructed which express wild-type ER-alpha and mutants Ser47Thr, Lys531 Glu, and Tyr537Asn.
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