1. Academic Validation
  2. Hyperactivation of MAPK Induces Tamoxifen Resistance in SPRED2-Deficient ERα-Positive Breast Cancer

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

  • Cancers (Basel). 2022 Feb 14;14(4):954. doi: 10.3390/cancers14040954.
Vasiliki Vafeiadou 1 Dina Hany 1 2 Didier Picard 1
Affiliations

Affiliations

  • 1 Département de Biologie Moléculaire et Cellulaire, Université de Genève, Sciences III, 1211 Genève 4, Switzerland.
  • 2 On leave from: Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria 21311, Egypt.
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.

Keywords

ERα; SPRED2; breast cancer; endocrine resistance; precision medicine; tamoxifen; ulixertinib.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15816
    99.95%, ERK1/3抑制剂
    ERK