Co-inhibition of mTORC1, HDAC and ESR1α retards the growth of triple-negative breast cancer and suppresses cancer stem cells

Abstract

Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer. It causes the majority of breast cancer-related deaths, which has been largely associated with the plasticity of tumor cells and persistence of cancer stem cells (CSCs). Conventional chemotherapeutics enrich CSCs and lead to drug resistance and disease relapse. Development of a strategy capable of inhibiting both bulk and CSC populations is an unmet medical need. Inhibitors against estrogen receptor 1, HDACs, or mTOR have been studied in the treatment of TNBC; however, the results are inconsistent. In this work, we found that patient TNBC samples expressed high levels of mTORC1 and HDAC genes in comparison to luminal breast cancer samples. Furthermore, co-inhibition of mTORC1 and HDAC with rapamycin and valproic acid, but neither alone, reproducibly promoted ESR1 expression in TNBC cells. In combination with tamoxifen (inhibiting ESR1), both S6RP phosphorylation and rapamycin-induced 4E-BP1 upregulation in TNBC bulk cells was inhibited. We further showed that fractionated CSCs expressed higher levels of mTORC1 and HDAC than non-CSCs. As a result, co-inhibition of mTORC1, HDAC, and ESR1 was capable of reducing both bulk and CSC subpopulations as well as the conversion of fractionated non-CSC to CSCs in TNBC cells. These observations were partially recapitulated with the cultured tumor fragments from TNBC patients. Furthermore, co-administration of rapamycin, valproic acid, and tamoxifen retarded tumor growth and reduced CD44high/+/CD24low/− CSCs in a human TNBC xenograft model and hampered tumorigenesis after secondary transplantation. Since the drugs tested are commonly used in clinic, this study provides a new therapeutic strategy and a strong rationale for clinical evaluation of these combinations for the treatment of patients with TNBC.

MicroRNA-645 targets urokinase plasminogen activator and decreases the invasive growth of MDA-MB-231 triple-negative breast cancer cells

“… 59 , 60 However, the prognosis and clinical outcomes of TNBC, which does not express estrogen receptors (ER), progesterone receptors (PR) or HER2, are far from satisfying. 61 , 62 Although TNBC only accounts for a small portion (10%–20%) of all breast cancer cases, it has a high mortality risk and is more aggressive than other breast cancer sub-types. 63 Given the absence of definitive therapeutic targets (ER, PR or HER2), only a few adjuvant treatments, such as conventional surgery, chemotherapy and radiotherapy, can provide any benefit for TNBC patients.…”

Antiproliferative activity and p53 upregulation effects of chalcones on human breast cancer cells

“…Formazan crystals were solubilised in dimethylsulfoxide (DMSO, Sigma Aldrich V R , St. Louis, MO), and absorbance rates were measured at 562 nm in ThermoPlate V R TP Reader. Chalcones 1,6,8,9,11,17,19, and 20 had the highest antiproliferative activity and were assayed against both cell lines at seven concentrations, ranging from 1.25 to 80 lM for IC 50 values determination.…”

“…We assayed analogues substituted by nitro (2), trifluoromethyl (3), cyano (4), and halogens (5-12). 3-Chloro-4'-aminochalcone (9) and 2-fluoro-4'aminochalcone (11) were the two most active compounds against MCF-7 line, with %MVC rates of 52.5 ± 6.7 and 50.3 ± 7.8, respectively. 3-Fluoro-4'-aminochalcone (8) was the most potent against MDA-MB-231 line, with %MVC of 73.3 ± 5.4.…”

“…This cancer has poor response to chemotherapy, particularly at metastatic sites, with survival rates below 2 years. Altogether, TNBC cancer has been considered the most severe and difficult to treat due to a lack of targeted therapy [10][11][12] .…”

Oncogenic miR-20b-5p contributes to malignant behaviors of breast cancer stem cells by bidirectionally regulating CCND1 and E2F1

“…Similarly, one study has demonstrated that miR-128-3p inhibits the stemlike cell features of BCSCs via inhibition of the Wnt signaling pathway by downregulating NEK2, which provides a new target for breast cancer treatment [31]. Then, another study indicates that CD24 and CD44 are cancer stem cells which can promote the development of breast cancer [32]. Many miRNAs have been shown to regulate the self-renewal and differentiation of CSCs, such as the let-7 miRNA family [33,34].…”