Hyperactivation of MAPK Induces Tamoxifen Resistance in SPRED2-Deficient ERα-Positive Breast Cancer

SIMPLE SUMMARY: Tamoxifen has been used for more than 40 years to treat breast tumors that are dependent on the hormone estrogen for their growth. However, resistance and recurrence of the tumors during the course of the treatment are common. Understanding the mechanisms that drive tamoxifen resistance and discovering new biomarkers for early detection are keys for designing appropriate personalized therapies. Here, we show that low levels of SPRED2 may be useful as a novel biomarker of tamoxifen resistance. We found that SPRED2 deficiency causes a hyperactivation of the mitogen-activated protein kinases (MAPKs) ERK1/ERK2, which in turn enhances estrogen signaling and diminishes the toxic effects of tamoxifen on breast cancer cells. Treatment with the ERK1/2 inhibitor, ulixertinib, could restore their sensitivity to tamoxifen. Therefore, we propose that patients with estrogen-dependent breast cancer characterized by low expression levels of SPRED2 may be candidates for a combination therapy with tamoxifen and ulixertinib. ABSTRACT: 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.