I've been getting this intermittently.  Clients accessing my published websites get a 404 - 12028 error message.  I've actually had this problem since ISA 2004 RTM was deployed, and I've mitigated it by setting "requests appear to come from ISA server" setting.

Perhaps this hotfix will help: http://support.microsoft.com/kb/919621/.  This hotfix actually covers 2 other issues.  So to just patch this specific problem, refer to the reference to: 917265 (http://support.microsoft.com/kb/917265/) Error message when client computers that are behind a proxy server access Web sites that are published by using ISA Server 2004: “404 Not Found. The requested item could not be located (12028)”

Consider the following scenario:
- You have multiple Web sites that are hosted on a back-end Web server.
- You publish the Web server by using Microsoft Internet Security and Acceleration (ISA) Server 2004.
- You use the Requests appear to come from original client option and the Forward the Original host header instead of the actual one [specified above] option to configure the Web publishing rule.

In this scenario, if you access the Web site from a client computer that is behind a proxy server that caches forward connections, you may receive an error message that resembles the following:
404 Not Found. The requested item could not be located (12028)

About time this was isolated and released.  It's been driving me insane for over a year.