Abstract P4-02-13: Social isolation promotes mammary cancer recurrence, increases IL6/JAK/STAT3 signaling and causes mitochondrial dysfunction in tamoxifen treated rats, and a traditional herbal mixture reverses all these changes
Authors: Andrade Fabia , Jin Lu , Clarke Robert , Wood Imani , Dutton MaryAnn , Anjorin Chezaray , Rubin Grace , Gao Audrey , Sengupta Surojeet , FitzGerald Kevin , Hilakivi-Clarke Leena 
Published: March 2022

BACKGROUND: Social isolation is associated with increased risk and mortality from many diseases, such as breast cancer. Socially isolated breast cancer survivors have a 43% higher risk of recurrence and a 64% higher risk of breast cancer-specific mortality than socially integrated survivors. Since Covid-19 has dramatically increased the incidence of social isolation, it is important to determine if social isolation affects the response to endocrine therapy and/or recurrence after the therapy is completed. Further, since previous studies indicate that social isolation increases circulating inflammatory cytokines, we investigated if an anti-inflammatory herbal mixture Jaeumkanghwa-tang (JEKHT) prevents the adverse effects of social isolation on breast cancer mortality. METHODS: Estrogen receptor positive mammary tumors were initiated with 7,12-dimethylbenz[a]anthracene. When a rat developed a palpable mammary tumor, it was either socially isolated (SI) by housing it singly or a rat was allowed to remain group-housed (GH). Tamoxifen (340ppm via diet) or tamoxifen + JEKHT (500ppm via drinking water) started when the first mammary tumor was detected. Tamoxifen administration ended when a complete response to this therapy had lasted for 9 weeks (corresponds to 5 years in women). Rats which received JEKHT during tamoxifen therapy continued to take it also after tamoxifen therapy ended. RESULTS: During tamoxifen therapy, social isolation non-significantly reduced the rate of complete responses to 21%, from 31% in GH group (p&gt;0.05). After the therapy was completed, SI significantly increased local mammary tumor recurrence (p&lt;0.001; 45% GH vs 75% SI). RNAseq analysis was performed in the mammary glands, since only tamoxifen resistant or recurring mammary tumors were available for analysis. Gene set enrichment analysis (GSEA) of transcriptome showed that the increased recurrence risk in socially isolated rats was associated with an enrichment of IL6/JAK/STAT3 signaling: this result was confirmed in the tumors. In addition, oxidative phosphorylation (OXPHOS) pathway was suppressed: the suppressed genes included those involved in mitochondrial pyruvate transport and conversion of pyruvate to acetyl CoA as well as genes in the TCA cycle and mediating electron transport in mitochondrial complexes I-IV. Despite the reduction in pyruvate transporting and converting genes, lactate levels or lactate dehydrogenase activity were not increased in socially isolated rats, indicating no changes in Warburg effect. Social isolation also increased the expression of inflammatory receptor for advanced glycation end-products (RAGE) (p≤0.05). Consumption of an anti-inflammatory JEKHT inhibited IL6/JAK/STAT3 signaling, upregulated OXPHOS signaling and prevented the increased risk of mammary cancer recurrence in socially isolated animals. The percentage of recurrences in the SI rats dropped from 75% without JEKHT to 22% with JEKHT (p&lt;0.001). CONCLUSION: Breast cancer mortality among socially isolated survivors may be most effectively prevented by focusing on the period following endocrine therapy using tools that inhibit IL6/JAK/STAT3 inflammatory cytokine signaling and correct disrupted OXPHOS and mitochondrial dysfunction.

Citation Format: Fabia Andrade, Lu Jin, Robert Clarke, Imani Wood, MaryAnn Dutton, Chezaray Anjorin, Grace Rubin, Audrey Gao, Surojeet Sengupta, Kevin FitzGerald, Leena Hilakivi-Clarke. Social isolation promotes mammary cancer recurrence, increases IL6/JAK/STAT3 signaling and causes mitochondrial dysfunction in tamoxifen treated rats, and a traditional herbal mixture reverses all these changes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-13.