Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Sep;42(3):1205-1213.
doi: 10.3892/or.2019.7219. Epub 2019 Jul 4.

Evaluation of the STAT3 inhibitor GLG‑302 for the prevention of estrogen receptor‑positive and ‑negative mammary cancers

Robert H Shoemaker  1 , Jennifer T Fox  1 , Margaret M Juliana  2 , Fariba L Moeinpour  2 , Clinton J Grubbs  2
Affiliations

Evaluation of the STAT3 inhibitor GLG‑302 for the prevention of estrogen receptor‑positive and ‑negative mammary cancers

Robert H Shoemaker et al. Oncol Rep. 2019 Sep.

Abstract

Signal transducer and activator of transcription 3 (STAT3) plays a key role in the transformation of normal cells to cancerous cells. Although inhibitors of STAT3 have been shown to suppress the growth of multiple cancer types in vitro and in vivo, such agents are of particular interest for the prevention of breast cancer, which affects over 200,000 women and claims more than 40,000 lives in the United States each year. In the present study, we employed the MMTV/Neu transgenic mouse model, which develops estrogen receptor (ER)‑negative, Neu‑overexpressing tumors, and the Sprague‑Dawley (SD) rat model, which develops ER‑positive tumors upon exposure to the carcinogen 7,12‑dimethylbenz[a]anthracene (DMBA), to test the efficacy of the STAT3 inhibitor GLG‑302 in the prevention of mammary cancer. Orally administered GLG‑302 and its trizma salt derivative reduced mammary cancer incidence, multiplicity, and tumor weights in female MMTV/Neu mice, and GLG‑302 reduced tumor multiplicity and weights in female DMBA‑treated rats. Consistent with the mechanism of action of STAT3 inhibitors, the reductions in mammary tumors were correlated with decreases in STAT3 phosphorylation and cell proliferation. These data suggest that GLG‑302 is a novel agent with potential for prevention of mammary cancer and support the further development of STAT3 inhibitors for this cause.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Effect of GLG-302 on the appearance of spontaneous mammary cancers in female MMTV/Neu mice and DMBA-treated rats. (A) When compared to the control group, none of the treatment groups in the MMTV/Neu mouse study (n=10–15/group) showed a significant difference in tumor latency. (B) For female Sprague-Dawley rats (n=15/group), there were no significant differences in tumor latency. The statistical analyses of the tumor multiplicity and incidence at the end of the studies are documented in Tables IA and B. DMBA, 7,12-dimethylbenz[a]anthracene; GLG-302, STAT3 inhibitor.
Figure 2.
Figure 2.
Effect of GLG-302 on the rate of proliferation of epithelial cells in the normal mammary glands of female MMTV/Neu mice and Sprague-Dawley rats. (A) Seven to eight-week old MMTV/Neu mice or (B) Sprague-Dawley rats were treated with different doses of GLG-302 by gavage. The error bars represent SEM. *P<0.05, a statistically significant difference from the control group. GLG-302, STAT3 inhibitor.
Figure 3.
Figure 3.
Effect of GLG-302/trizma salt on the appearance of DMBAinduced mammary cancers in female MMTV/Neu mice. When compared to the control group, only the highest (500 mg/kg BW/day) treatment group showed a significant difference in tumor latency (P=0.012). The statistical analyses of tumor multiplicity and incidence at the end of the study are described in Table II. n=18-23/group. DMBA, 7,12-dimethylbenz[a]anthracene; GLG-302, STAT3 inhibitor.
Figure 4.
Figure 4.
Effect of GLG-302/trizma salt on the rate of proliferation and p-STAT3 expression in the normal epithelial cells of female MMTV/Neu mice and in mammary cancers excised from female MMTV/Neu mice. (A and B) Seven- to eight-week old mice (n=3–4/group) were treated with different doses of GLG-302 by gavage. Mammary tissue was analyzed for (A) Ki-67 and (B) p-STAT3 expression. (C and D) Tumors (n=5/group) excised from the mice in the 500 mg/kg BW/day treatment group in Fig. 3 were analyzed for (C) Ki-67 and (D) p-STAT3 expression. In all panels, error bars represent SEM. *P<0.05, a statistically significant difference from the control group. Representative images used for the quantification are shown to the right of each graph (magnification, ×20). GLG-302, STAT3 inhibitor; p-STAT3, phosphorylated signal transducer and activator of transcription 3.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Al Rabadi L, Bergan R. A way forward for cancer chemoprevention: Think local. Cancer Prev Res (Phila) 2017;10:14–35. doi: 10.1158/1940-6207.CAPR-16-0194. - DOI - PubMed
    1. Port ER, Montgomery LL, Heerdt AS, Borgen PI. Patient reluctance toward tamoxifen use for breast cancer primary prevention. Ann Surg Oncol. 2001;8:580–585. doi: 10.1007/s10434-001-0580-9. - DOI - PubMed
    1. Ropka ME, Keim J, Philbrick JT. Patient decisions about breast cancer chemoprevention: A systematic review and meta-analysis. J Clin Oncol. 2010;28:3090–3095. doi: 10.1200/JCO.2009.27.8077. - DOI - PMC - PubMed
    1. Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, Dey S, Sung B. Signal transducer and activator of transcription-3, inflammation, and cancer: How intimate is the relationship? Ann N Y Acad Sci. 2009;1171:59–76. doi: 10.1111/j.1749-6632.2009.04911.x. - DOI - PMC - PubMed
    1. Leslie K, Lang C, Devgan G, Azare J, Berishaj M, Gerald W, Kim YB, Paz K, Darnell JE, Albanese C, et al. Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res. 2006;66:2544–2552. doi: 10.1158/0008-5472.CAN-05-2203. - DOI - PubMed

Publication types

MeSH terms

Substances