The Role of Lipolysis Stimulated Lipoprotein Receptor in Breast Cancer and Directing Breast Cancer Cell Behavior

Abstract

The claudin-low molecular subtype of breast cancer is of particular interest for clinically the majority of these tumors are poor prognosis, triple negative, invasive ductal carcinomas. Claudin-low tumors are characterized by cancer stem cell-like features and low expression of cell junction and adhesion proteins. Herein, we sought to define the role of lipolysis stimulated lipoprotein receptor (LSR) in breast cancer and cancer cell behavior as LSR was recently correlated with tumor-initiating features. We show that LSR was expressed in epithelium, endothelium, and stromal cells within the healthy breast tissue, as well as in tumor epithelium. In primary breast tumor bioposies, LSR expression was significantly correlated with invasive ductal carcinomas compared to invasive lobular carcinomas, as well as ERα positive tumors and breast cancer cell lines. LSR levels were significantly reduced in claudin-low breast cancer cell lines and functional studies illustrated that re-introduction of LSR into a claudin-low cell line suppressed the EMT phenotype and reduced individual cell migration. However, our data suggest that LSR may promote collective cell migration. Re-introduction of LSR in claudin-low breast cancer cell lines reestablished tight junction protein expression and correlated with transepithelial electrical resistance, thereby reverting claudin-low lines to other intrinsic molecular subtypes. Moreover, overexpression of LSR altered gene expression of pathways involved in transformation and tumorigenesis as well as enhanced proliferation and survival in anchorage independent conditions, highlighting that reestablishment of LSR signaling promotes aggressive/tumor initiating cell behaviors. Collectively, these data highlight a direct role for LSR in driving aggressive breast cancer behavior.

Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer

“…For example, over-expression of LSR enhances cell proliferation and migration, as well as stimulates cancer-stem cell related properties such as survival in anchorage-independent conditions [21]. We also show that LSR expression significantly correlates with ERα expression in primary breast cancer biopsies [21]. In the current study, we show that tamoxifen-resistant breast cancer cell lines also express LSR and are sensitive to iota toxin-induced cytotoxicity.…”

“…However, an emerging problem has been that ~33% of patients given tamoxifen therapy for five years develop recurrent tumors, and of those, 26% subsequently die [49-51]. Previous studies in our laboratory show that LSR is positively correlated with ERα expression [21]. Tamoxifen-resistant breast cancers are derived from ERα-positive tumors, and thus are likely to have high expression of LSR making them potential candidates for successful treatment with iota toxin.…”

Downregulation of lipolysis‑stimulated lipoprotein receptor promotes cell invasion via claudin‑1‑mediated matrix metalloproteinases in human endometrial cancer

“…TRIC expression is associated with Snail-induced EMT in gastric carcinoma cells and shows a negative correlation with the degree of differentiation in pancreatic ductal adenocarcinomas (13,14). The expression of the tTJ protein LSR may be associated with tumor progression and the degree of differentiation in addition to TRIC (16).…”

“…LSR signaling also promotes aggressive/tumor-initiating cell behaviors in breast cancer (16). In addition, our recent study revealed that small interfering RNA (siRNA)-mediated knockdown of LSR promoted cell invasion in human endometrial cancer cells.…”

Loss of tricellular tight junction protein LSR promotes cell invasion and migration via upregulation of TEAD1/AREG in human endometrial cancer

“…Furthermore, TRIC expression in gastric carcinoma cells is negatively regulated by snail-induced epithelial-mesenchymal transition (EMT)13. It is thought that the tTJ protein LSR is also associated with tumor progression14. Knockdown of LSR increases cell motility and invasion by bladder cancer cells15.…”