Regulation of Breast Carcinoma Progression by the Alpha-6 Integrins
Annual rept. 1 Sep 1999-31 Aug 2000
BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA
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During the third year of this career development award, we have continued to make progress in determining the contribution of the alpha6 integrin receptors to breast carcinoma progression. In previous work we had established that the alpha6Beta1 receptor contributes to the growth and survival of breast carcinoma metastases. In addition, we had demonstrated that expression of the Beta4 integrin subunit in breast carcinoma cell lines that lack this integrin subunit increases their invasive potential. Since submitting the initial proposal, we have demonstrated that the ability of the alpha6beta4 integrin to promote carcinoma invasion involves its activation of phosphoinositide 3-OH kinase PI3K and the small GTP- binding protein Rac. We have also identified PKC-epsilon as a critical effector for invasion and we have determined that it contributes to cell motility through the regulation of lamellae organization and function. We have identified 155-1 and 155-2 as intermediate adapter proteins in the activation of 513K by the alpha6 integrin and we have identified specific domains of the IRS proteins that are involved. We have also established that the alpha6beta4receptor can cooperate with the IGF-lR to activate the IRS proteins and promote IGF-lR signalling.
- Anatomy and Physiology
- Medicine and Medical Research