Spine‑specific downregulation of LAPTM5 expression promotes the progression and spinal metastasis of estrogen receptor‑positive breast cancer by activating glutamine‑dependent mTOR signaling

Abstract

Estrogen receptor-positive (ER + ) breast cancer (BC) is a malignancy that is prone to metastasis to the spine, which is difficult to treat and often results in poor prognosis. However, the mechanism underlying the tumorigenesis and spinal metastasis of ER + BC remains unclear. Lysosomal protein transmembrane 5 (LAPTM5) has been reported as a tumor suppressor in several types of cancer, but its role in ER + BC has not been described. Here, by analyzing a gene sequencing dataset and ER + BC tissues, tumor-adjacent normal tissues and spinal metastatic tissues from patients and mouse models, we found that LAPTM5 expression is negatively related to the progression and spinal metastasis of ER + BC. Subsequently, in vitro experiments demonstrated that downregulation of LAPTM5 expression promoted the proliferation, migration, and chemoresistance of ER + BC cells by activating glutamine-dependent mTOR signaling. A high level of CX3CL1 could inhibit LAPTM5 expression, explaining how ER + BC metastasized to the spine. Thus, we found that LAPTM5 functions as a tumor suppressor in ER + BC and that the CX3CL/CX3CR1/LAPTM5/glutamine axis mediates the spinal metastasis of ER + BC. This axis may be a promising therapeutic target for ER + BC.

CX3CL1 and its receptor CX3CR1 interact with RhoA signaling to induce paclitaxel resistance in gastric cancer

“…CX3CL1 is originally translated as a transmembrane protein but can be proteolytically processed to produce a soluble chemokine and has been demonstrated to signal via its receptor CX3CR1 [ 16 ]. More specifically, a high level of CX3CL1 has been revealed to inhibit the expression of lysosomal protein transmembrane 5, explaining how estrogen receptor-positive breast cancer metastasized to the spine [ 17 ]. Furthermore, the expression of CX3CL1 and CX3CR1 in GC tissues was higher than those in adjacent tissues and was promoted in GC tissues from the perineural invasion-positive group compared to the perineural invasion-negative group [ 18 ].…”

LAPTM5 regulated by FOXP3 promotes the malignant phenotypes of breast cancer through activating the Wnt/β‑catenin pathway

“…Moreover, a previous study found that LAPTM 4 beta (LAPTM4B), which belongs to the same lysosomal membrane protein as LAPTM5, was upregulated in breast cancer, and its high expression was positively related to TNM stage and lymph node metastasis (33). Recently, Meng et al (34) found that LAPTM5 regulated the development and spinal metastasis of ER-positive breast cancer through the glutamine-dependent mTOR signaling, while the present study demonstrated that LAPTM5, which is affected by the transcription factor FOXP3, could contribute to the tumor progression of breast cancer via the Wnt/β-catenin signaling pathway (Fig. 7).…”

Symptomatic bone marrow metastases in breast cancer: A retrospective cohort study

“…The reported articles did not analyze the specific sites of bone metastases. We found that the weight-bearing bone (spine, 26 cases) was the most common site of metastasis, which may be because the level of CXC3L1/CXC3R1 in the spine bone is higher than that in other bones, which can promote the adhesion and migration of breast cancer cells ( 13 ).…”