Modulation of Cathepsin-D and pS2 Protein Levels in Human Breast Cancer Cell Lines

Abstract

Cathepsin-D and pS2 are two estrogen-regulated proteins in human breast cancer cell lines. They have been considered possible prognostic factors in breast cancer, but results have been contradictory. To better understand the regulation of these proteins, we investigated the role of estradiol (E₂), serum, and growth factors in hormone-dependent (MCF-7, ZR75.1) and hormone-independent (MDAMB-231, BT20) breast cancer cell lines. E₂ treatment in serum-free conditions increased intracellular and secreted levels of pS2 in ZR75.1 and in MCF-7, secreted levels only of cathepsin-D in MCF-7, and both levels of cathepsin-D in ZR75.1. Insulin-like growth factor I (IGF-I) and progesterone receptors were also stimulated by E₂, whereas the estrogen receptor was down-regulated. Following treatment with epidermal growth factor (EGF), secreted pS2 levels doubled only in MCF-7 cells. IGF-I did not modify cathepsin-D or pS2 levels in either cell line, but caused an increase in its own receptor. Cathepsin-D and pS2 doubled in MCF-7 cells grown in medium supplemented with denatu-rated serum, but estrogen regulation of these proteins was still maintained. Cathepsin-D was expressed in MDAMB-231 and BT20, but its levels were modified by neither E₂ nor growth factor treatment. Conversely, neither cell line expressed detectable levels of pS2 before or after treatment. In conclusion, our results show that in different types of breast cancer cells, some estrogen-regulated proteins (e.g. pS2) are also regulated by growth factors such as EGF and other unknown serum factors. This may account for the contradictory results obtained regarding the prognostic relevance of cathepsin-D and pS2.

Modulation of the estrogen-regulated proteins cathepsin D and pS2 by opioid agonists in hormone-sensitive breast cancer cell lines (MCF7 and T47D): Evidence for an interaction between the two systems

“…A menstrual cycle-dependent expres-sion of pS2 was observed, while cathepsin D as well as estrogen receptor status was not modified [Khan et al, 1997], indicating a possible differential estrogen regulation of the two proteins [Rajah et al, 1996]. Indeed, previous results indicated that estrogen treatment of hormone-responsive cells (MCF7 and ZR75.1) increased intracellular and secreted pS2 levels in both lines and intracellular (MCF7, ZR75.1) and secreted (ZR 75.1) levels of cathepsin D, indicating further a differential regulation of production and/or secretion [Cappelletti et al, 1996]. This differential regulation was further indicated by the results of the present study.…”

Human neural stem cells restore spatial memory in a transgenic Alzheimer’s disease mouse model by an immunomodulating mechanism

“…This could be related to an enriched population of stem cells, as NCAM and sVCAM-1 are known to be related to neural stem cell survival, proliferation, and migration ( Shan, 2013 ; Klein et al, 2016 ), whereas increases in the protease cathepsin D are associated with improved amyloid beta clearance ( Gao et al, 2020 ; Kim et al, 2020 ). This effect could also be related to hNSC secretion of IGF-1, shown to promote survival of NCAM-expressing neural progenitors ( Gago et al, 2003 ; Monzo et al, 2013 ), which can mediate and induce cathepsin D expression ( Cappelletti et al, 1996 ; Wang et al, 2000 ).…”