Integrins comprise a large family of cell surface receptors with critical roles in cancer cell proliferation, invasion and metastatic potential. Experiments carried out during the last funding cycle have uncovered a novel pathway of prostate cancer progression mediated by the av?6 integrin. We have found that av?6 is not expressed in human and mouse normal prostate but becomes significantly upregulated in preneoplastic lesions, prostatic adenocarcinoma (AdCa) and bone metastasis. Mechanistically, av?6 expression results in upregulation of androgen receptor (AR) activity via a JNK-mediated pathway. Our findings show, for the first time, that integrins modulate AR activity. In this pathway, we have identified survivin, a bifunctional regulator of cell division and inhibitor of apoptosis, as one of the critical downstream effector molecule which becomes upregulated in cells expressing av?6. Our in vivo data demonstrate that expression of av?6 results in enhanced tumor growth and metastatic dissemination as compared to a different av integrin, av?3. Expression of av?6 also causes tumor-mediated osteolysis, a crucial step in prostate cancer metastasis. Since av?3 has been shown to promote bone gain in prostate cancer metastatic lesions, we hypothesize that the extent of bone-lesion formation is controlled by the relative expression levels of av?6 and av?3. Finally, we show that these integrins'expression is regulated by two different transcription factors activated by TGF?: av?6 is induced via Smad3 activation, whereas av?3 expression is mediated by Runx2. We have formulated a unifying hypothesis that av?6 integrin functions as an integrator of multiple signaling pathways to promote early and late phases of prostate cancer progression. This hypothesis will be tested in the present renewal application by the following aims.
In Aim 1, the molecular mechanisms by which av?6 activates AR will be investigated.
In Aim 2, we will investigate in vivo the role of av?6 in prostate cancer progression in a mouse model of prostate cancer;for this purpose, we will use the prostate specific Pten-null mouse model which develops PIN, cancer and metastasis.
In Aim 3, to credential av integrins as molecular targets in prostate cancer bone lesion therapies, we will dissect the pathways by which av?6 and av?3 contribute to bone disease in vivo. Our long-term objective is to take advantage of this newly generated knowledge to develop novel molecular antagonists of prostate cancer progression.
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