Identification of ER Negative Tumors in Which MAPK Inhibition Restores Both ER Expression and Anti-Estrogen Responses.
Authors: El-Ashry D. , Brinkman J. , Miller P. 
Published: December 2010

Abstract
Background: Approximately 35% of breast cancer lacks expression of the estrogen receptor α (ERα). ERα negative breast cancer carries a poorer prognosis compared to ERα+ breast cancer, but more importantly, it precludes the use of less toxic anti-estrogen therapies. Our previous data suggest that many ERα- breast tumors have the potential to express ERα, but ERα expression is repressed by hyperactive MAPK as a result of altered growth factor signalling pathways. We have shown that hyperactive MAPK results in down-regulation of ERα and treatment that inhibits MAPK activity results in re-expression of ERα protein and restoration of anti-estrogen sensitivity in both in vitro cell line and ex vivo primary culture model systems.Results: Using a panel of 9 primary cultures established from ERα- breast tumors, we have examined the incidence of MAPK inhibition mediated restoration of ERα expression. Of the 9 primary cultures examined to date, 5 are from triple negative tumors and 4 are from ERα-/PR-/H2N+ tumors. Of the 5 triple negative cultures analyzed, 3 re-express ERα upon MAPK inhibition, while 2 do not, and all 4 ERα-/H2N+ cultures re-express ERα. Although each of these primary cultures exhibited wide variation in the level of hyperactive MAPK, in those that re-expressed ERα, it was successful inhibition of MAPK activity that led to the re-expression of ERα. To establish determinants of the subset of ERα- breast tumors in which MAPK inhibition will restore ERα expression and more importantly, those in which MAPK inhibition restores both ERα expression and anti-estrogen responses, we have performed both proteomic and genomic profiling of these 9 primary cultures in the absence and presence of MAPK inhibition. Key differences between those primary cultures that re-express ERα vs those that do not, and interestingly, between triple negative primary cultures that re-express ERα vs those that express Her2 and re-express ERα upon MAPK inhibition have been identified. The role of these in determining restoration of anti-estrogen responses as well are being established.Discussion: Our overall goal is to understand the mechanisms underlying ERα- breast cancer and to develop novel therapies for ERα- breast cancer based on the re-expression of ERα and restoration of anti-estrogen responses. Having shown that hyperactive MAPK can repress ERα expression, and more importantly that inhibition of MAPK can restore functional ERα expression, we now need to establish the subsets of ERα- breast cancer in which each of this mechanism is responsible for the lack of ERα expression. This knowledge will allow us to determine which ERα- breast cancer patients may benefit from the combined inhibition of MAPK and ERα. The ability to use drugs with low toxicity to re-express ERα in ERα- tumors and thus render them sensitive to anti-estrogens would be a major leap forward in the treatment of ERα- breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 404.