Astrocytes promote progression of breast cancer metastases to the brain via a KISS1-mediated autophagy

Abstract

Formation of metastases, also known as cancer dissemination, is an important stage of breast cancer (BrCa) development. KISS1 expression is associated with inhibition of metastases development. Recently we have demonstrated that BrCa metastases to the brain exhibit low levels of KISS1 expression at both mRNA and protein levels. By using multicolor immunofluorescence and coculture techniques here we show that normal adult astrocytes in the brain are capable of promoting metastatic transformation of circulating breast cancer cells localized to the brain through secretion of chemokine CXCL12. The latter was found in this study to downregulate KISS1 expression at the post-transcriptional level via induction of microRNA-345 (MIR345). Furthermore, we demonstrated that ectopic expression of KISS1 downregulates ATG5 and ATG7, 2 key modulators of autophagy, and works concurrently with autophagy inhibitors, thereby implicating autophagy in the mechanism of KISS1-mediated BrCa metastatic transformation. We also found that expression of KISS1 in human breast tumor specimens inversely correlates with that of MMP9 and IL8, implicated in the mechanism of metastatic invasion, thereby supporting the role of KISS1 as a potential regulator of BrCa metastatic invasion in the brain. This conclusion is further supported by the ability of KISS1, ectopically overexpressed from an adenoviral vector in MDA-MB-231Br cells with silenced expression of the endogenous gene, to revert invasive phenotype of those cells. Taken together, our results strongly suggest that human adult astrocytes can promote brain invasion of the brain-localized circulating breast cancer cells by upregulating autophagy signaling pathways via the CXCL12-MIR345- KISS1 axis.

microRNAs Orchestrate Pathophysiology of Breast Cancer Brain Metastasis: Advances in Therapy

“…In this regard, miR-345 was the only identified miR that directly targets KISS1, which is induced via the treatment of CXCL12 or CCL2 proteins [125][126][127]. They experimentally confirmed the binding of miR-345 in stably transfected KISS1 3'UTR in MDA231Br cells with astrocyte conditioned media treatment or in the presence of individual recombinant CCl2 or CXCL12 proteins [72]. Interestingly, the downregulation of KISS1 has a stimulating effect on ATG5 expression associated with autophagosome maturation.…”

“…MiR-122 reduces glucose consumption in stromal cells and allows more glucose to be accessible to cancer cells, hence facilitating the formation of the metastatic niche and cancer cell growth [74]. b CXCL12 or CCL2 secreted by astrocytes increases the level of miR-345 via CXCR4, which negatively regulates the expression of KISS1 and promotes invasion and survival in the brain [72]. c MiR-19a mediates the suppression of PTEN in cancer cells secreted by activated astrocytes.…”

Autophagy-associated circRNA circCDYL augments autophagy and promotes breast cancer progression

“…Though breast cancer exhibits good prognosis, some breast cancer patients still suffer tumor progression. One of the emerging concepts to promote progression of breast cancer is autophagy [4,[8][9][10][11]. It is now known that the dysregulation of autophagy promotes progression of breast cancer.…”

“…hypoxia, starvation) and helps sustain their survival [7]. It has been reported that autophagy promotes survival, proliferation, metastasis, and invasion of BC cells via regulating autophagy associated genes and non-coding RNAs [4,[8][9][10][11][12]. However, the underlying mechanisms, especially non-coding RNAs, in regulating autophagy of BC progression are not yet fully elucidated.…”

The Signaling Duo CXCL12 and CXCR4: Chemokine Fuel for Breast Cancer Tumorigenesis

“…CXCL12 downregulates the expression of Kiss1 in breast cancer cells, a gene associated with metastasis inhibition. The expression of Kiss1 in human breast cancer specimens inversely correlates with levels of matrix metalloproteinase-9 (MMP-9) and IL-8—genes implicated in metastatic invasion [ 117 ]. CAFs have also been implicated in brain metastasis.…”