Both high-protein and low-GI regimens increase body fat loss, but cardiovascular risk reduction is optimized by a high-carbohydrate, low-GI diet.
Tryptophan-2,3-dioxygenase (TDO2), a rate-limiting enzyme in the tryptophan catabolism pathway, is induced in triple-negative breast cancer (TNBC) by inflammatory signals and anchorage-independent conditions. TNBCs express extremely low levels of the miR-200 family compared with estrogen receptor-positive (ER) breast cancer. In normal epithelial cells and ER breast cancers and cell lines, high levels of the family member miR-200c serve to target and repress genes involved in epithelial-to-mesenchymal transition (EMT). To identify mechanism(s) that permit TNBC to express TDO2 and other proteins not expressed in the more well-differentiated ER breast cancers, miRNA-200c was restored in TNBC cell lines. The data demonstrate that miR-200c targeted TDO2 directly resulting in reduced production of the immunosuppressive metabolite kynurenine. Furthermore, in addition to reversing a classic EMT signature, miR-200c repressed many genes encoding immunosuppressive factors including , and Restoration of miR-200c revealed a mechanism, whereby TNBC hijacks a gene expression program reminiscent of that used by trophoblasts to suppress the maternal immune system to ensure fetal tolerance during pregnancy. Knowledge of the regulation of tumor-derived immunosuppressive factors will facilitate development of novel therapeutic strategies that complement current immunotherapy to reduce mortality for patients with TNBC.
Mutations in ESR1 that confer constitutive estrogen receptor alpha (ER) activity in the absence of ligand are acquired by ≥40% of metastatic breast cancers (MBC) resistant to adjuvant aromatase inhibitor (AI) therapy. To identify targetable vulnerabilities in MBC, we examined steroid hormone receptors and tumorinfiltrating immune cells in metastatic lesions with or without ER mutations. ER and progesterone receptor (PR) were significantly lower in metastases with wild-type (WT) ER compared with those with mutant ER, suggesting that metastases that evade AI therapy by mechanism(s) other than acquiring ER mutations lose dependency on ER and PR. Metastases with mutant ER had significantly higher T regulatory and Th cells, total macrophages, and programmed death ligand-1 (PD-L1)-positive immune-suppressive macrophages than those with WT ER. Breast cancer cells with CRISPR-Cas9-edited ER (D538G, Y537S, or WT) and patient-derived xenografts harboring mutant or WT ER revealed genes and proteins elevated in mutant ER cells, including androgen receptor (AR), chitinase-3-like protein 1 (CHI3L1), and IFN-stimulated genes (ISG). Targeting these proteins blunted the selective advantage of ER-mutant tumor cells to survive estrogen deprivation, anchorage independence, and invasion. Thus, patients with mutant ER MBC might respond to standard-of-care fulvestrant or other selective ER degraders when combined with AR or CHI3L1 inhibition, perhaps with the addition of immunotherapy.Significance: Targetable alterations in MBC, including AR, CHI3L1, and ISG, arise following estrogen-deprivation, and ER-mutant metastases may respond to immunotherapies due to elevated PD-L1 þ macrophages.See related article by Arnesen et al., p. 539
Triple-negative breast cancer (TNBC) is an aggressive subtype, with a peak recurrence rate within the first few years after diagnosis. Few targeted therapies are available to treat this breast cancer subtype, defined by the lack of estrogen receptor (ER) and progesterone receptor and without amplification of human epidermal growth factor receptor 2 (HER2). Although cell cycle cyclin-dependent kinase (CDK) 4/6 inhibitors are approved for treatment of ER-positive (ER+) breast cancer, they have not proven effective as monotherapy in patients with TNBC. The androgen receptor (AR) has emerged as a therapeutic target in a subset of TNBCs and with significant clinical benefit observed in multiple trials. The purpose of this study was to investigate the preclinical activity of the CDK4/6 inhibitor, abemaciclib, in combination with an agent that targets both androgen biosynthesis and AR activity, seviteronel, using TNBC cell lines expressing high AR, cell line xenografts, and an AR-positive (AR+), androgen-responsive TNBC patient-derived xenograft (PDX). Single-cell RNA sequencing demonstrated heterogeneity in AR levels, even in a highly AR+ cell line, and identified cell cycle pathway activation in ARHigh- versus ARLow-expressing cells. Combination treatment with the cell cycle CDK4/6 inhibitor, abemaciclib, and seviteronel showed synergy in an AR+ TNBC model compared with each drug alone. Although cell cycle inhibitors are FDA approved for use in ER+ breast cancer, our studies suggest that they may also be effective in AR+ TNBC, perhaps combined with AR-targeted agents.
Many immune suppressive mechanisms utilized by triple negative breast cancer (TNBC) are regulated by oncogenic epithelial-to-mesenchymal transition (EMT). How TNBC EMT impacts innate immune cells is not fully understood. To determine how TNBC suppresses antitumor macrophages, we used microRNA-200c (miR-200c), a powerful repressor of EMT, to drive mesenchymal-like mouse mammary carcinoma and human TNBC cells toward a more epithelial state. MiR-200c restoration significantly decreased growth of mouse mammary carcinoma Met-1 cells in culture and in vivo. Cytokine profiling of Met-1 and human BT549 cells revealed that miR-200c upregulated cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), promoted M1 antitumor macrophage polarization. Cytokines upregulated by miR-200c correlated with an epithelial gene signature and M1 macrophage polarization in BC patients and predicted a more favorable overall survival for TNBC patients. Our findings demonstrate that immunogenic cytokines (e.g., GM-CSF) are suppressed in aggressive TNBC, warranting further investigation of cytokine-based therapies to limit disease recurrence.
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