Breast cancer is the number one cause of
cancer-related mortality in women worldwide. Most
breast tumors depend on the expression of the
estrogen receptor α (ERα) for their growth. For this reason, targeting ERα with antagonists such as
tamoxifen is the
therapy of choice for most patients. Although initially responsive to
tamoxifen, about 40% of the patients will develop resistance and ultimately a recurrence of the disease. Thus, finding new
biomarkers and therapeutic approaches to treatment-resistant
tumors is of high significance. SPRED2, an inhibitor of the MAPK signal transduction pathway, has been found to be downregulated in various
cancers. In the present study, we found that SPRED2 is downregulated in a large proportion of
breast-cancer patients. Moreover, the knockdown of SPRED2 significantly increases cell proliferation and leads to
tamoxifen resistance of
breast-cancer cells that are initially
tamoxifen-sensitive. We found that resistance occurs through increased activation of the MAPKs ERK1/ERK2, which enhances the transcriptional activity of ERα. Treatment of SPRED2-deficient
breast cancer cells with a combination of the ERK 1/2 inhibitor
ulixertinib and
4-hydroxytamoxifen (4-OHT) can inhibit cell growth and proliferation and overcome the induced
tamoxifen resistance. Taken together, these results indicate that SPRED2 may also be a
tumor suppressor for
breast cancer and that it is a key regulator of cellular sensitivity to
4-OHT.