Chunk #64 — 4. WIP1 SUPPRESSES THE STRESS RESPONSE: UPDATE — 4.5. Wip1 attenuates the response to oncogenic stress and promotes tumorigenesis — 4.5.1. Cooperation of Wip1 with oncogenes in tumorigenesis
Several recent in vitro studies have described a role for Wip1 in tumorigenesis. As mentioned above, Wip1 plays an important role in intestinal tumorigenesis through regulation of stem cell apoptosis, and furthermore, Zhang et al. showed that Wip1 also plays an important role in mammary tumor stem cell proliferation (36). Although Wip1 expression was slightly increased in primary tumor cells from MMTV-Erbb2 mice, Wip1 expression in mammary tumor stem cells isolated from these mice exhibited a 3-to-5 fold increase. On the other hand, expression of miR-16, a negative regulator of Wip1 (see section 3.1.1), was reduced by about 70-to-80% in mammary tumor stem cells whereas it was only slightly reduced in the whole population of primary tumor cells (36). These results suggest that inhibition of miR-16 leads to Wip1 overexpression in mammary tumor stem cells. Furthermore, overexpression of miR-16 or depletion of Wip1 inhibited mammary tumor stem cell proliferation. Wip1 overexpression also partially reversed the miR-16-dependent inhibition of proliferation, indicating that Wip1 facilitates mammary tumor stem cell proliferation (36). Although the mechanism is unknown, it would be interesting to test whether Wip1 inhibits p53-dependent apoptosis in mammary tumor stem cells, as is the case in intestinal stem cells (65).
