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HSulf?1 and palbociclib exert synergistic antitumor effects on RB?positive triple?negative breast cancer.

ABSTRACT: Human sulfatase?1 (HSulf?1) is emerging as a novel prognostic biomarker in breast cancer. Previous studies demonstrated HSulf?1 to function as a negative regulator of cyclin D1 in breast cancer. Accumulating preclinical evidence is supporting the efficacy of cyclin?dependent kinase (CDK) 4/6 inhibitors against the luminal androgen receptor sub?type of triple?negative breast cancer (TNBC). It was therefore hypothesized that HSulf?1 may cooperate with CDK4/6 inhibitors to control cell cycle progression in breast cancer cells. HSulf?1 expression was found to be downregulated in TNBC tissues and cell lines compared with that in healthy tissues and non?breast cancer cell lines, respectively. High levels of HSulf?1 expression was also found to be associated with increased progression?free survival and overall survival in patients with TNBC. Functionally, it was demonstrated that HSulf?1 served as tumor suppressor in TNBC by inducing cell cycle arrest and apoptosis whilst inhibiting proliferation, epithelial?mesenchymal transition, migration and invasion. Subsequent overexpression of HSulf?1 coupled with treatment with the CDK4/6 inhibitor palbociclib exhibited a synergistic antitumor effect on retinoblastoma (RB)?positive TNBC. Further studies revealed the mechanism underlying this cooperative antiproliferative effect involved to be due to the prohibitive effects of HSulf?1 on the palbociclib?induced accumulation of cyclin D1 through AKT/STAT3 and ERK1/2/STAT3 signaling. Taken together, findings from the present study not only suggest that HSulf?1 may be a potential therapeutic target for TNBC, but also indicate that combinatorial treatment could be an alternative therapeutic option for RB?positive TNBC, which may open novel perspectives.

SUBMITTER: Chen F

PROVIDER: S-EPMC7252455 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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HSulf‑1 and palbociclib exert synergistic antitumor effects on RB‑positive triple‑negative breast cancer.

Chen Fengxia F Zhang Zhicai Z Yu Yihan Y Liu Qiuyu Q Pu Feifei F

International journal of oncology 20200504 1

Human sulfatase‑1 (HSulf‑1) is emerging as a novel prognostic biomarker in breast cancer. Previous studies demonstrated HSulf‑1 to function as a negative regulator of cyclin D1 in breast cancer. Accumulating preclinical evidence is supporting the efficacy of cyclin‑dependent kinase (CDK) 4/6 inhibitors against the luminal androgen receptor sub‑type of triple‑negative breast cancer (TNBC). It was therefore hypothesized that HSulf‑1 may cooperate with CDK4/6 inhibitors to control cell cycle progre ...[more]

PMID: 32377705

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Project description:BackgroundTriple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks sensitivity to chemotherapy, endocrine therapy or targeted therapy. CDK4/6 inhibitors, combined with endocrine therapy, have been shown to be effective in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Therefore, we investigated whether the CDK4/6 inhibitor palbociclib (PD) could enhance the effects of cisplatin (CDDP) on TNBC.MethodsThe effects of different drug regimens consisting of PD and CDDP on MDA-MB-231 and RB-knockdown MDA-MB-231 (sh-MDA-MB-231) cells were assessed in vitro and in vivo. MDA-MB-468 and RB-overexpressing MDA-MB-468 cells were used to assess the effect of the PD-CDDP regimens in vitro. Immunoblotting illustrated the role of the cyclin D1/RB/E2F axis signalling pathway.ResultsPD induced G1 phase cell cycle arrest in the MDA-MB-231 cell line. However, synchronous treatment with PD and CDDP for 24 h, treatment with PD for 24 h followed by CDDP and treatment with CDDP for 24 h followed by PD had no influence on MDA-MB-231 cell apoptosis. We further investigated the effect of PD or CDDP withdrawal on the effects of sequential treatment and found that PD treatment for 48 h followed by withdrawal for 48 h and subsequent CDDP treatment (PD-CDDP) significantly increased apoptosis and inhibited the cell viability and colony formation of MDA-MB-231 cells, while with other regimens, PD and CDDP had an additive or antagonistic response. The preferential use of PD increased DNA damage induced by CDDP, as measured through γH2AX immunofluorescence. These findings were not observed in sh-MDA-MB-231 cells, and experiments to assess cell function in MDA-MB-468 and RB-overexpressing MDA-MB-468 cells yielded similar results, which indicated that PD enhanced the sensitivity of TNBC cells to CDDP in an RB-dependent manner. In vivo, compared with single drug treatment, combination treatment inhibited tumour growth and Ki-67 expression in MDA-MB-231 xenograft models. Western blot analysis revealed that PD enhanced sensitivity to CDDP through the CDK4/6-cyclin D1-RB-E2F pathway.ConclusionsPre-treatment with PD synchronized the tumour cell cycle through the CDK4/6-cyclin D1-RB-E2F pathway, which increased the antitumour effect of CDDP. Thus, PD-CDDP might be an effective treatment for RB-proficient TNBC patients.

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HSulf?1 and palbociclib exert synergistic antitumor effects on RB?positive triple?negative breast cancer.

Publications

HSulf‑1 and palbociclib exert synergistic antitumor effects on RB‑positive triple‑negative breast cancer.

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