Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis

Abstract

Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor β (ERβ), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ERβ could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ERβ agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1β in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ERβ could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis.

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

“…In vitro studies with TNBC cell lines have shown that ERβ prevents invasiveness but does not affect proliferation (38)(39)(40). Studies with TNBC cell lines showed that ERβ can affect invasiveness by secretion of cystatins (41) and can increase innate immunity (42).…”

Sex and Gender Disparities in Melanoma

“…Administration of the ERβ agonist LY500307 in female mice, previously i.v. injected with melanoma cells, decreases lung nodules [55]. Oral administration of TAM [56] and EDX [57] exert inhibitory effects on tumor metastatization into the mouse lungs.…”

“…Many different cell types express estrogen receptors (α and β ERs) (i.e., epithelial cells, lymphoid tissues and immune cells) that allow estrogen binding and signal activation [82][83][84]. Direct implication of estrogen-dependent effects on innate immunity have been recently evidenced in a syngeneic mouse model of melanoma where in vivo studies showed that the estrogen agonist erteberel, activating the ERβ signaling, was capable of augmenting innate immunity and suppressing lung metastatic colonization by recruitment of antitumor neutrophils to the metastatic niche [55]. On the contrary, castration in male mice led to an increased autoimmune response by the induction of the major histocompatibility complex II (MHCII) [85].…”

The role of estrogen receptor beta in breast cancer

“…It must be pointed out that ERβ plays an important role in the cell behavior and extracellular matrix (ECM) composition of breast cancer cells and may have an effect on important chemokine receptors [83,84]. It is also involved in the beclin1-dependent autophagic cascade [85].…”