Abstract B33: Target STAT3 signaling for the prevention of ER-negative breast cancer

Estrogen receptor (ER)-negative breast cancer counts for approximately 30-40% of breast cancer cases. Although a large portion of ER-positive breast cancer can be prevented with ER modulators and aromatase inhibitors, these drugs fail to prevent any ER-negative breast cancers or the rest, resistant ER-positive breast cancers. Particularly, there is no targeted therapy for preventing ER-negative breast cancer, due to its lack of ER expression and resulting non-responsive nature to ER modulators. Thus, prevention of ER-negative breast cancer is an unmet need and challenge, and it is urgent to identify novel molecular targets and develop effective chemopreventive agents for the prevention of all types of breast cancers. The STAT3 transcription factor is a major contributor in the development of multiple cancers since STAT3 signaling is required for the growth of stem cell-like cancer cells. In our preliminary studies, we found that STAT3 is activated in human mammary epithelial cells that overexpress tert and ras oncogenes, in the premalignant mammary glands of MMTV-erbB2 mice before mammary tumors develop, and in human breast premalignant hyperplasia lesion and ductal carcinoma in situ (DCIS). Thus, STAT3 activation is an early molecular event in breast carcinogenesis and therefore, STAT3 represents a promising, new molecular target for the prevention of breast cancer. We hypothesized that STAT3 is a driving factor in breast cancer development, and blockade of STAT3 activity will prevent ER-negative breast cancer formation. However, STAT3 is traditionally termed as “un-druggable” target. Previous strategies of inhibiting STAT3 activity did not sufficiently block STAT3 activation in cancer cells due to their limited potency, poor solubility and bioavailability. We therefore developed orally active STAT3 inhibitors for cancer prevention use. Our newly developed STAT3 inhibitors suppress STAT3 activation and ER-negative breast cancer cell proliferation at low μM to nM potency, induce apoptosis, and suppress xenograft tumor growth in vivo. The inhibitors also show low toxicity and superior aqueous solubility as well as oral bioavailability. We treated the MMTV-erbB2 transgenic mice that develop spontaneous ER-negative mammary tumors, at the age of 3 months when mammary glands were fully developed. The STAT3 inhibitor, HJC0152, was given via oral gavage for 5 days per week at a dosage of 25 mg/kg for 2-8 months. While our experiments are still ongoing, we have started to observe significant chemopreventive effect of HJC0152 on reducing oncogene-induced ER-negative mammary tumor formation in MMTV-Neu model. These studies suggest that inhibition of STAT3 activation is a promising strategy for the prevention of ER-negative breast cancer. This work was supported by Grants P50 CA097007, P30DA028821, and R21MH093844 (J.Z.) from NIH, R. A. Welch Foundation Chemistry and Biology Collaborative Grant from Gulf Coast Consortia (GCC), John Sealy Memorial Endowment Fund (J.Z.), the DFI Seed Funding Program from MD Anderson Cancer Center (Q.S.). Citation Format: Zhengduo Yang, Haijun Chen, Chunyong Ding, Christopher Wild, Jia Zhou, Qiang Shen. Target STAT3 signaling for the prevention of ER-negative breast cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B33.