Akademik Veri Yönetim Sistemi
JOURNAL OF INVESTIGATIVE MEDICINE, cilt.73, sa.2, ss.218-228, 2025 (SCI-Expanded)
Triple-positive breast cancer (TPBC) is a type of breast cancer that overexpresses estrogen receptor (ER), progesterone
receptor (PR), and human epidermal growth factor receptor-2 (HER2). Dysregulation of ER signaling has been implicated in
the pathogenesis of breast cancer. ERa activation triggers the production of second messengers, including cAMP, leading to
the activation of signals such as PI3K/AKTor Ras/MAPK. Ruxolitinib is a specific inhibitor of JAK1/JAK2. MK-2206 is an allosteric
inhibitor of the Akt. The limitations of the use of ruxolitinib and MK-2206 as single agents necessitate the development
of combination therapies with other drugs. This study is the first to investigate the effects of combining ruxolitinib with MK-
2206 on MAPK and PI3K/AKT signaling in BT474 breast cancer cells. In addition, this work aimed to increase the anticancer
effects of cotreatment with MK-2206 and ruxolitinib. Ruxolitinib, MK-2206, and their combination reduced cell viability in a
dose- and time-dependent manner, as determined by MTT assays after 48 h of treatment. Colony formation and wound
healing assays demonstrated that MK-2206 exhibited a synergistic anti-proliferative effect. The effects of ruxolitinib, MK-
2206, and their combination on PI3K/AKTand MAPK signaling were assessed via western blotting. Ruxolitinib and MK-2206
combined treatment inhibit cell death in BT474 cells by downregulating ERa, Src-1, ERK1/2, SAPK/JNK, and c-Jun. Our
results revealed the relationships among the ERa, PI3K/AKT, and MAPK signaling pathways in ER+ breast cancer cells.
Understanding the interactions among ERa, PI3K-AKT-mTOR, and MAPK could lead to novel combination therapies.