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Int. J. Mol. Sci. 2017, 18(11), 2305; https://doi.org/10.3390/ijms18112305

Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer

1
UCLA School of Nursing, University of California at Los Angeles, Los Angeles, CA 90095, USA
2
UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90095, USA
3
Department of Medicine, Division of Cancer Research and Training, Charles Drew University School of Medicine and Science, Los Angeles, CA 90059, USA
4
UCLA David Geffen School of Medicine, Department of Medicine, Division of Hematology-Oncology, University of California at Los Angeles, Los Angeles, CA 90095, USA
5
Department of Biology, California State University Channel Islands, Camarillo, CA 93012, USA
6
Department of Integrative Ecology and Evolutionary Biology and Physiology, UCLA College of Life Sciences, University of California at Los Angeles, Los Angeles, CA 90095, USA
7
Department Physiological, UCLA College of Life Sciences, University of California at Los Angeles, Los Angeles, CA 90095, USA
*
Author to whom correspondence should be addressed.
Received: 26 September 2017 / Revised: 25 October 2017 / Accepted: 25 October 2017 / Published: 2 November 2017
(This article belongs to the Special Issue IGFs in Health and Disease)
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Abstract

Triple-negative breast cancer (TNBC) occurs in 10–15% of all breast cancer patients, yet it accounts for about half of all breast cancer deaths. There is an urgent need to identify new antitumor targets to provide additional treatment options for patients afflicted with this aggressive disease. Preclinical evidence suggests a critical role for insulin-like growth factor-2 (IGF2) and androgen receptor (AR) in regulating TNBC progression. To advance this work, a panel of TNBC cell lines was investigated with all cell lines showing significant expression of IGF2. Treatment with IGF2 stimulated cell proliferation in vitro (p < 0.05). Importantly, combination treatments with IGF1R inhibitors BMS-754807 and NVP-AEW541 elicited significant inhibition of TNBC cell proliferation (p < 0.001). Based on Annexin-V binding assays, BMS-754807, NVP-AEW541 and enzalutamide induced TNBC cell death (p < 0.005). Additionally, combination of enzalutamide with BMS-754807 or NVP-AEW541 exerted significant reductions in TNBC proliferation even in cells with low AR expression (p < 0.001). Notably, NVP-AEW541 and BMS-754807 reduced AR levels in BT549 TNBC cells. These results provide evidence that IGF2 promotes TNBC cell viability and proliferation, while inhibition of IGF1R/IR and AR pathways contribute to blockade of TNBC proliferation and promotion of apoptosis in vitro. View Full-Text
Keywords: triple-negative breast cancer; insulin-like growth factor-2; androgen receptor; BMS-754807; NVP-AEW541; enzalutamide; IGF1R/IR inhibition; IGF2 signaling; AKT kinase; apoptosis triple-negative breast cancer; insulin-like growth factor-2; androgen receptor; BMS-754807; NVP-AEW541; enzalutamide; IGF1R/IR inhibition; IGF2 signaling; AKT kinase; apoptosis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Hamilton, N.; Austin, D.; Márquez-Garbán, D.; Sanchez, R.; Chau, B.; Foos, K.; Wu, Y.; Vadgama, J.; Pietras, R. Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2017, 18, 2305.

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