PMID- 36316775 OWN - NLM STAT- MEDLINE DCOM- 20221103 LR - 20221105 IS - 1465-542X (Electronic) IS - 1465-5411 (Print) IS - 1465-5411 (Linking) VI - 24 IP - 1 DP - 2022 Oct 31 TI - Steroid receptor coactivator-3 inhibition generates breast cancer antitumor immune microenvironment. PG - 73 LID - 10.1186/s13058-022-01568-2 [doi] LID - 73 AB - BACKGROUND: The tumor immune microenvironment (TIME) generated by cancer-infiltrating immune cells has a crucial role in promoting or suppressing breast cancer progression. However, whether the steroid receptor coactivator-3 (SRC-3) modulates TIME to progress breast cancer is unclear. Therefore, the present study evaluates whether SRC-3 generates a tumor-promoting TIME in breast tumors using a syngeneic immune-intact mouse model of breast cancer. METHODS: We employed E0771 and 4T1 breast cancer in immune-intact syngeneic female C57BL/6 and BALB/c mice, respectively. SI-2, a specific small-molecule inhibitor of SRC-3, was administered daily (2.5 mg/kg) to E0771 and 4T1 breast tumor-bearing immune-intact mice. In addition, SRC-3 knockdown (KD)-E0771 and SRC-3 KD-4T1 cells and their parental breast cancer cells were injected into their syngeneic immune-intact female mice versus immune-deficiency mice to validate that the host immune system is required for breast tumor suppression by SRC-3 KD in immune-intact mice. Furthermore, tumor-infiltrating immune cells (such as CD4+, CD8+, CD56+, and Foxp3+ cells) in E0771 and 4T1 breast cancers treated with SI-2 and in SRC-3 KD E0771 and 4T1 breast cancers were determined by immunohistochemistry. Additionally, cytokine levels in SI-2-treated and SRC-3 KD E0771 breast tumors and their control cancers were defined with a Mouse Cytokine Array. RESULTS: SRC-3 inhibition by SI-2 significantly suppressed the progression of breast cancer cells (E0771 and 4T1) into breast cancers in immune-intact syngeneic female mice. SRC-3 KD-E0771 and -4T1 breast cancer cells did not produce well-developed tumors in immune-intact syngeneic female mice compared to their parental cells, but SRC-3 KD breast cancers were well developed in immune-defective host mice. SRC-3 inhibition by SI-2 and SRC-3 KD effectively increased the numbers of cytotoxic immune cells, such as CD4+ and CD8+ T cells and CD56+ NK cells, and Interferon gamma (Ifng) in breast cancers compared to vehicle. However, SI-2 treatment reduced the number of tumor-infiltrating CD4+/Foxp3+ regulatory T (Treg) cells compared to vehicle treatment. In addition, SRC-3 inhibition by SI-2 and SRC-3 KD increased C-X-C motif chemokine ligand 9 (Cxcl9) expression in breast cancer to recruit C-X-C motif chemokine receptor 3 (Cxcr3)-expressing cytotoxic immune cells into breast tumors. CONCLUSIONS: SRC-3 is a critical immunomodulator in breast cancer, generating a protumor immune microenvironment. SRC-3 inhibition by SI-2 or SRC-3 KD activates the Cxcl9/Cxcr3 axis in breast tumors and enhances the antitumor immune microenvironment to suppress breast cancer progression. CI - (c) 2022. The Author(s). FAU - Han, Sang Jun AU - Han SJ AD - Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. sjhan@bcm.edu. AD - Duncan Cancer Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. sjhan@bcm.edu. FAU - Sung, Nuri AU - Sung N AD - Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. FAU - Wang, Jin AU - Wang J AD - Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, 77030, USA. FAU - O'Malley, Bert W AU - O'Malley BW AD - Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. AD - Duncan Cancer Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. FAU - Lonard, David M AU - Lonard DM AD - Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. dlonard@bcm.edu. AD - Duncan Cancer Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. dlonard@bcm.edu. LA - eng GR - R01 CA250503/CA/NCI NIH HHS/United States GR - R01 CA207701/CA/NCI NIH HHS/United States GR - P01 DK059820/DK/NIDDK NIH HHS/United States GR - R01 HD007857/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20221031 PL - England TA - Breast Cancer Res JT - Breast cancer research : BCR JID - 100927353 RN - 0 (Cytokines) RN - 0 (Forkhead Transcription Factors) RN - EC 2.3.1.48 (Ncoa3 protein, mouse) RN - EC 2.3.1.48 (Nuclear Receptor Coactivator 3) SB - IM MH - Animals MH - Female MH - Mice MH - Cell Line, Tumor MH - Cytokines/metabolism MH - Forkhead Transcription Factors MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - *Neoplasms MH - *Tumor Microenvironment MH - *Nuclear Receptor Coactivator 3/metabolism PMC - PMC9620627 OTO - NOTNLM OT - Antitumor immunity OT - Breast cancer OT - C-X-C motif chemokine ligand 9 OT - E0771 cells OT - Interleukin 1 receptor antagonist OT - Steroid receptor coactivator inhibitor COIS- BWO, DML, and JW are the co-founders of CoActigon Inc. JW is the co-founder of Chemical Biology Probes LLC. EDAT- 2022/11/02 06:00 MHDA- 2022/11/03 06:00 PMCR- 2022/10/31 CRDT- 2022/11/01 00:53 PHST- 2022/02/07 00:00 [received] PHST- 2022/10/17 00:00 [accepted] PHST- 2022/11/01 00:53 [entrez] PHST- 2022/11/02 06:00 [pubmed] PHST- 2022/11/03 06:00 [medline] PHST- 2022/10/31 00:00 [pmc-release] AID - 10.1186/s13058-022-01568-2 [pii] AID - 1568 [pii] AID - 10.1186/s13058-022-01568-2 [doi] PST - epublish SO - Breast Cancer Res. 2022 Oct 31;24(1):73. doi: 10.1186/s13058-022-01568-2.