Defining the role of progesterone receptor and progestin in luminal breast cancer cells

Abstract

Progesterone is a steroid hormone essential for the reproduction and the development of the mammary gland. Its effects are mediated by progesterone receptor (PR) which is induced by estrogen in most target tissues. In humans and mice, PR is expressed as two major isoforms: PRA and PRB. Although progesterone has been implicated in breast cancer its role in the development of breast cancer remains controversial. There is evidence for the increased risk of breast cancer incidence in post-menopausal women receiving estrogen plus progestin replacement therapy compared to estrogen therapy alone. However, progestin demonstrated therapeutic benefits for metastatic breast cancer. In laboratory studies, progestin can stimulate or inhibit cell growth depending on experimental conditions and cell models. It has been reported that progesterone inhibits estrogen-induced growth of ER and PR-positive luminal breast cancer cells MCF-7 in xenograft model and this is mediated by modulating the activity of ER. However, the role of PR in mediating the effect of progestin in this most commonly used ER and PR-positive model is controversial. This is partly due to the fact that PR expression is estrogen-dependent and the level of estrogen-induced PR is relatively low. As a result, the effect of progestin treatment is often marginal. In order to better understand PRmediated effect of progestin in luminal breast cancer, the main aim of the study was to establish MCF-7 luminal breast cancer cells overexpressing PRB and define the molecular and cellular aspects of PRB-mediated effect of progestin in this MCF-7 cell model. We hypothesize that progestin exerts inhibitory effect on MCF-7 cells expressing PR independent estrogen. The study demonstrated that progestin R5020 causes drastic cell growth inhibition. More interestingly, R5020 completely abolished estrogen-induced cell growth. Furthermore, the R5020-treated cells in three dimensional (3D) Matrigel culture were unable to form proper mammospheres and almost the entire population underwent apoptosis after 1-2 weeks in 3D culture. Thus, progestin R5020 strongly suppresses the growth of luminal breast cancer cells when there is abundant expression of PRB. Taken together, our study demonstrated powerful anti-tumoral effect of R5020 on breast cancer cells expressing high levels of PR a nd future in vivo studies could lead to improved outcomes in breast cancer patients. Chapter 1. Introduction 1.1 Nuclear receptors Nuclear receptors (NRs) are part of a large family of ligand-activated transcription factors (Tsai and O'Malley 1994, Glass and Rosenfeld 2000). Based on their different mechanisms of action and ligand properties, NRs superfamily can be classified into three groups (hormone, metabolic and orphan NRs) (Mangelsdorf, Thummel et al. 1995). These transcription factors directly regulate genes that are involved in numerous physiological processes, such as homeostasis, reproduction, development, and metabolism (Mangelsdorf, Thummel et al. 1995, Xiao, Wang et al. 2013). NRs exert their func...

Notes on the 10th–11th-century relations of female jewellery found in the Carpathian Basin with South-Eastern Europe reflected by two types of jewellery

“…A similar age was assumed by Serbian researchers in connection with the fi nd from the site Grocka. 323 This object Type is rarer compared to Type II. Based on the currently known fi nds, its main distribution area was the territory of former Pannonia 324 and the neighbouring territories (fi g. 22).…”

The liability for the damage for discharging the items or for spilling the liquids from the premises

“…Po ovom autoru, kada su u pitanju štete od izbacivanja stvari ili prolijevanja tekućina iz prostorija, riječ je o objektivnoj odgovornosti zasnovanoj na teoriji rizika, prema kojoj svako treba da snosi rizik stvari čiji je sopstvenik ili držalac i iz koje izvlači koristi. 36 Prof. dr Stevan Jakšić takođe smatra da je odgovornost imaoca stana za štete od izbacivanja predmeta ili prosipanja tekućina po svojoj pravnoj prirodi objektivna, dakle odgovornost bez obzira na krivicu. Imalac stana je odgovoran za štetu bez obzira da li je prisutan ili odsutan iz stana, bez obzira da li je kriv ili nije, da li je počinilac uračinljiv ili nije.…”