Overview of the therapeutic strategies for ER positive breast cancer.

Estrogen Receptor is the driving transcription factor in about 75% of all breast cancers, which is the target of endocrine therapies, but drug resistance is a common clinical problem. ESR1 point mutations at the ligand binding domain are frequently identified in metastatic tumor and ctDNA (Circulating tumor DNA) derived from ER positive breast cancer patients with endocrine therapies. Although endocrine therapy and CDK4/6 inhibitor therapy have demonstrated preclinical and clinical benefits for breast cancer, the development of resistance remains a significant challenge and the detailed mechanisms, and potential therapeutic targets in advanced breast cancer yet to be revealed. Since a crosstalk between tumor and tumor microenvironment (TME) plays an important role to grow tumor and metastasis, this effect could serve as key regulators in the resistance of endocrine therapy and the transition of breast cancer cells to metastasis. In this article, we have reviewed recent progress in endocrine therapy and the contribution of TME to ER positive breast cancer.

Cytokines secreted by stromal cells in TNBC microenvironment as potential targets for cancer therapy.

In triple-negative breast cancer (TNBC), the lack of therapeutic markers and effective targeted therapies result in an incurable metastatic disease associated with a poor prognosis. Crosstalks within the tumor microenvironment (TME), including those between cancer and stromal cells, affect the tumor heterogeneity, growth, and metastasis. Previously, we have demonstrated that IL-6, IL-8, and CCL5 play a significant role in TNBC growth and metastasis. In this study, we performed a systematic analysis of cytokine factors secreted from four stromal components (fibroblasts, macrophages, lymphatic endothelial cells, and blood microvascular endothelial cells) induced by four TNBC cell types. Through bioinformatic analysis, we selected putative candidates of secreted factors from stromal cells, which are involved in EMT activity, cell proliferation, metabolism, and matrisome pathways. Among the candidates, LCN2, GM-CSF, CST3, IL-6, IL-8, and CHI3L1 are ranked highly. Significantly, Lipocalin-2 (LCN2) is upregulated in the crosstalk of stromal cells and four different TNBC cells. We validated the increase of LCN2 secreted from four stromal cells induced by TNBC cells. Using a specific LCN2 antibody, we observed the inhibition of TNBC cell growth and migration. Taken together, these results propose secreted factors as molecular targets to treat TNBC progression via crosstalk with stromal components.