Elevated estrogen receptor β expression in triple negative breast cancer cells is associated with sensitivity to doxorubicin by inhibiting the PI3K/AKT/mTOR signaling pathway

Abstract

Based on its pathological characteristics, breast cancer is a highly heterogeneous disease. Triple negative breast cancer (TNBC) is an aggressive subtype, and due to a lack of effective therapeutic targets, patients with TNBC do not significantly benefit from endocrine or anti-HER2 therapy. Conventional chemotherapy has been regarded as the only systemic therapy option for TNBC, but its therapeutic efficacy remains limited. Estrogen receptor β (ERβ) has been identified as a tumor suppressor in TNBC. Therefore, the aim of the present study was to identify the role of ERβ in regulating the response to chemotherapy, and to investigate its underlying mechanism in TNBC. MDA-MB-231 and BT549 cells were treated with doxorubicin (DOX), liquiritigenin [Liq, (Chengdu Biopurify Phytochemicals, Ltd.); a specific ERβ agonist], or a combination of DOX and Liq in vitro. The effects of various treatments on cell viability and proliferation were measured using the Cell Counting Kit-8 and colony-formation assays, respectively. MDA-MB-231 and ERβ knockdown (ERβ-KD) MDA-MB-231 cells were selected for the establishment of ERα-/ERβ+ and ERα-/ERβ-cell models, respectively. The two cell models were treated with DOX, Liq or a combination of DOX and Liq. The effects of the treatment on the PI3K/AKT/mTOR signaling pathway were evaluated by assessing the protein expression levels of AKT and mTOR using western blot analysis. Low Liq concentrations increased the sensitivity of MDA-MB-231 and BT549 cells to DOX. Moreover, the synergistic effect of Liq and DOX treatment was associated with the inhibition of the PI3K/AKT/mTOR signaling pathway in MDA-MB-231 cells, and the effect was ERβ-dependent. The results suggested that elevated ERβ expression was associated with sensitivity to doxorubicin by inhibiting the PI3K/AKT/mTOR signaling pathway; therefore, the combined use of conventional chemotherapeutic drugs with ERβ agonists may serve as an effective therapy for TNBC.

ERβ in Triple-Negative Breast Cancer: Emerging Concepts and Therapeutic Possibilities

“…In TNBCs, increased ERβ1 expression correlates with downregulation of pAKT, which represents a favorable prognostic marker for the overall and disease-freesurvival [11]. In TNBC cells, high levels of ERβ are associated with increased sensitivity to doxorubicin, which is controlled by the activation of the PI3K/AKT/mTOR pathway [52]. Triggering MDA-MB-231 and BT549 cell lines, with a specific agonist (liquiritigenin) for ERβ, increases the sensitivity to doxorubicin, a chemotherapeutic agent.…”

“…In both TNBC cell lines, combinatorial treatment with liquiritigenin and doxorubicin showed a stronger effect than that exerted by each drug in monotherapy. Analysis of the molecular mechanisms has shown that combinatorial treatment causes a strong inhibition of the PI3K/AKT/mTOR pathway and this mechanism is correlated to ERβ expression [52].…”

Light at night and risk of breast cancer: a systematic review and dose–response meta-analysis

“…In Italy, there were an estimated 55,000 new cases in 2020 [ 2 ], and while incidence is increasing, mortality rates have significantly decreased across the years. Several factors appear to be involved in both etiology and prognosis of this malignancy, including selected genes, ageing, family history, reproductive factors, long-term use of postmenopausal female hormones, lifestyle [ 3 , 4 ], and environmental factors such as exposure to chemical endocrine disruptors [ 5 – 9 ].…”

Actin-Like Protein 8 Promotes the Progression of Triple-Negative Breast Cancer via Activating PI3K/AKT/mTOR Pathway

“… 17 In fact, many PI3K/AKT/mTOR pathway regulators are acquiring a growing interest in TNBC treatment. 18 , 19 …”