Src: a potential target for the treatment of triple-negative breast cancer

Tryfonopoulos, Dimitrios; Walsh, Siún; Collins, Denis M.; Flanagan, Louise; Quinn, Cecily; Corkery, B.; McDermott, Enda; Evoy, Denis; Pierce, Aisling; O’Donovan, Norma; Crown, John; Duffy, Michael J.

doi:10.1093/annonc/mdq757

Cited by 126 publications

(113 citation statements)

References 22 publications

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“…However, Src inhibitor alone does not appear to achieve therapeutic effects in clinical trials. Finn et al demonstrated that the Src family inhibitor dasatinib alone showed only limited anticancer effects in a phase II clinical trial of triple negative breast cancer patients (38); combination with chemotherapy medication may improve the therapeutic effects (39). Our results also suggested that P4+PP1 combined treatment significantly inhibited the migration and invasion of lung adenocarcinoma A549 cells; P4 or PP1 alone showed limited effects.…”

Section: Molecular Pathways Involved In P4+pp1/mprα Signalingsupporting

confidence: 60%

Progesterone inhibits the migration and invasion of A549 lung cancer cells through membrane progesterone receptor α-mediated mechanisms

et al. 2013

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Abstract. Lung cancer is the leading cause of cancer morbidity and mortality in the world. The incidence of lung cancer, particularly lung adenocarcinoma, is increasing in women compared to men. The role of sex hormones in the development of lung cancer has attracted substantial interest, but remains largely unknown. In this study, we demonstrated that membrane progesterone receptor α (mPRα) was expressed in a lung adenocarcinoma cell line, A549, and was located on the cell membrane. In additional experiments, we found that mPRα functioned as an essential mediator for progesterone (P4)-induced inhibitory effects on cell migration and invasion of A549 cells. Furthermore, PP1 (an Src pathway inhibitor), when co-incubated with P4, synchronously enhanced the inhibitory effects of P4 on cell migration and invasion. To explore the mechanisms of inhibition, we found that P4 and PP1 induced a cascade of molecular signaling events, such as dephosphorylation of focal adhesion kinase (FAK) and downregulation of matrix metalloproteinase 9 (MMP-9). Our study provides a mechanistic view on the effects of P4 through mPRα→Src/FAK relevant pathways in human lung adenocarcinoma cells and may aid in the development of novel therapeutic tools for the treatment of lung cancer. IntroductionLung cancer is the leading cause of morbidity and mortality in malignant tumors. Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancer cases. Epidemic studies reveal gender differences in NSCLC patients, particularly in lung adenocarcinoma. Women are more susceptible to smoke or other environmental factors (1), in view of the fact that estrogen and progesterone are well-known prognostic factors for breast, endometrial and ovarian cancer, suggesting a possible involvement of gender-dependent factors in the pathogenesis and/or development of NSCLCs (2).Sex hormones and their receptors have been the focus of considerable cancer research. Among sex steroids, estrogens play an important role in the development of breast and endometrial carcinoma, whereas androgens significantly contribute to the development of prostate cancer (3). By contrast, progesterone generally promotes differentiation and inhibits cellular proliferation through the nuclear progesterone receptor (nPR) (4). Previous studies showed that progesterone-mediated growth inhibition was mainly preceded by decreased expression of cyclins and/or induction of cyclin-dependent kinase inhibitors (5-7). Administration of progestins, including medroxyprogesterone acetate, is currently used as an endocrine therapy in breast and endometrial carcinoma patients (8,9). During embryogenesis, sex hormones influence the development of lung tissue, but during adulthood, the lung is not a target organ for sex hormones. Notably, female adenocarcinoma has a better prognosis than male lung cancer or other female pathologic types of lung cancer, indicating gender as an independent prognostic factor (10). It is reported that progesterone can mediate growth inhibition in PR-positive tumors in mice th...

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Section: Molecular Pathways Involved In P4+pp1/mprα Signalingsupporting

confidence: 60%

Progesterone inhibits the migration and invasion of A549 lung cancer cells through membrane progesterone receptor α-mediated mechanisms

et al. 2013

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“…Because kinases are crucial for cancer cell survival, mitosis, migration and invasion, much research has been focused on developing inhibitors against them (6)(7)(8). Rapidly proliferating tumors like TNBCs rely on tight temporal regulation of the cell cycle and centrosome duplication.…”

Section: Introductionmentioning

confidence: 99%

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

et al. 2013

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Breast cancer is the most common solid tumor and the second most common cause of death in women. Despite a large body of literature and progress in breast cancer research, many molecular aspects of this complex disease are still poorly understood, hindering the design of specific and effective therapeutic strategies. To identify molecules important in breast cancer progression and metastasis, we tested the in vivo effects of inhibiting the functions of various kinases and genes involved in the regulation/modulation of the cytoskeleton by downregulating them in mouse PyMT mammary tumor cells and human breast cancer cell lines. These kinases and cytoskeletal regulators were selected based on their prognostic values for breast cancer patient survival. PyMT tumor cells in which a selected gene was stably knocked down were injected into the tail veins of mice and the formation of tumors in the lungs was monitored. One of several genes found to be important for tumor growth in lungs was Nek2, a cell cycle-related protein kinase. Furthermore, Nek2 was also important for tumor growth in the mammary fat pad.In various human breast cancer cell lines, Nek2 knockdown induced aneuploidy and cell cycle arrest that led to cell death. Significantly, the breast cancer cell line most sensitive to Nek2 depletion was of the triple negative breast cancer subtype. Our data indicate that Nek2 plays a pivotal role in breast cancer growth at primary and secondary sites, and thus may be an attractive and novel therapeutic target for this disease.

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“…As mentioned above, a number of studies have demonstrated that SRC, Raf, and VEGFR2 could be potential targets for the treatment of TNBC (13,18,34,35). The SRC/Raf inhibitor, SKLB646, indeed showed a nice selective inhibition of TNBC cell lines bearing an overexpression of SRC and mutant Raf, MD-MB-231, and MD-MB-435 (36,37).…”

Section: Discussionmentioning

confidence: 96%

“…Abnormal activation or amplification of SRC has been detected in TNBC and demonstrated to play a role in proliferation, migration, and invasion of breast cancer cell lines (11,12). Furthermore, a number of recent studies have shown that dysregulation of SRC is strongly associated with tumor metastasis and poor prognosis in TNBC (13,14). SRC therefore represents a rational molecular target for TNBC.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of a Novel Orally Available SRC/Raf/VEGFR2 Inhibitor, SKLB646, in the Treatment of Triple-Negative Breast Cancer

Zheng

Zhang

Chen

et al. 2016

Molecular Cancer Therapeutics

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Triple-negative breast cancer (TNBC) is the most aggressive and deadly breast cancer subtype. To date, chemotherapy is the only systemic therapy and prognosis remains poor. Herein, we report the preclinical evaluation of SKLB646 in the treatment of TNBC; SKLB646 is a novel multiple kinase inhibitor developed by us recently. This compound potently inhibited SRC and VEGFR2 with IC 50 values of 0.002 mmol/L and 0.012 mmol/L, respectively. It also considerably inhibited B-Raf and C-Raf with IC 50 values of 0.022 and 0.019 mmol/L, respectively. It exhibited significant antiproliferation and antiviability activities against TNBC cell lines. Studies of mechanism of action indicated that SKLB646 inhibited the activation of SRC signaling and blocked the MAPK signaling through inhibiting the Raf kinases. Interestingly, SKLB646 dose dependently downregulated the expression of Fra1, a transcriptional factor that plays a critical role in the epithelial-to-mesenchymal transition. In addition, SKLB646 could inhibit HUVEC proliferation, migration, and invasion. It effectively blocked the formation of intersegmental vessels in zebrafish embryos and displayed considerable antiangiogenic effects in the tumorinduced neovascularization zebrafish model. In TNBC xenograft models, SKLB646 suppressed the tumor growth in a dosedependent manner. Moreover, SKLB646 could remarkably inhibit TNBC cell migration and invasion in vitro. Furthermore, in an experimental lung metastasis model, the overall survival time of groups treated with SKLB646 was much longer compared with the control-, dasatinib-, and paclitaxel-treated groups. In a preliminary pharmacokinetic study, SKLB646 showed good pharmacokinetic properties. Taken together, the preclinical data show that SKLB646 could be a promising lead compound for the treatment of TNBC.

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Src: a potential target for the treatment of triple-negative breast cancer

Abstract: We conclude that dasatinib with cisplatin is a rational drug combination for testing in triple-negative breast cancer.

Cited by 126 publications

References 22 publications

Progesterone inhibits the migration and invasion of A549 lung cancer cells through membrane progesterone receptor α-mediated mechanisms

Progesterone inhibits the migration and invasion of A549 lung cancer cells through membrane progesterone receptor α-mediated mechanisms

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

Preclinical Evaluation of a Novel Orally Available SRC/Raf/VEGFR2 Inhibitor, SKLB646, in the Treatment of Triple-Negative Breast Cancer

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