Retinoic acid modulates prolactin receptor expression and prolactin-induced STAT-5 activation in breast cancer cells in vitro

Abstract

Summary Two recent papers demonstrate that prolactin plays an important role in the induction and progression of mammary tumours. Retinoids have been shown to be potent inhibitors of breast carcinogenesis. We studied expression of prolactin receptor mRNA in human breast cancer cell lines MCF-7, SKBR-3, T47D and BT-20 treated with and without retinoids using Northern blot and a quantitative polymerase chain reaction (PCR) method. In all cell lines, all-trans-and 9-cis-retinoic acid, as well as the retinoic acid receptor γ (RAR-γ) selective agonists CD2325 and CD437 (1 µM), were able to down-regulate prolactin receptor. After 1 h, a significant reduction was detectable and maximal effect was achieved after 24 h of treatment. Pretreatment with retinoic acid also reduced the prolactin-/prolactin receptordependent signal transduction and activation of transcription 5 (STAT-5) activation in T47D cells. Cycloheximide failed to abrogate the retinoic acid-induced decline in prolactin receptor mRNA levels, indicating that this effect was not dependent upon continuing protein synthesis. Similarly, no change in the stability of prolactin receptor mRNA was observed during 12 h of retinoic acid treatment. In conclusion, our results demonstrate that retinoids are able to inhibit the expression of prolactin receptor message, which encodes an important growth factor receptor in breast cancer cells. This action could be responsible for the anti-tumour effects of retinoids.

The biochemical and morphological alterations following administration of melatonin, retinoic acid and Nigella sativa in mammary carcinoma: an animal model

“…2003). This finding may be explained by (a) the inhibitory effect of these substances on the release of pituitary hormones, particularly, prolactin (Mel); (b) inhibition of the expression of prolactin receptor (RA) (Widschwendter et al . 1999); (c) inhibition of oestrogen‐receptor activity (RA); and (d) antioxidant activity and interference with the DNA synthesis coupled with enhancement of detoxification processes (Mel, RA and NS) (Ali et al .…”

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

“…Unlike adaphostin (cf., section 8.2), 403 does not seem to increase ROS in the cancer cells . The wealth of studies covering the scope of cellular model systems sensitive to the cell cycle-modifying and apoptosis-inducing actions of 403 cover human lung cancer cells, − leukemias, − hepatoma cell lines, , prostate cancer cells, − breast cancer cell cultures, − ovarian carcinoma, − myeloma, , human bronchial epithel cells, , neuroblastoma, glioblastoma, , head and neck squamous carcinoma, normal mammary epithelial cells, malignant human epidermal keratinocytes, nontumorigenic keratinocytes, cutaneous squamous cell carcinoma, melanoma, − and primary microglia from rats, showing 403 ’s capability to regulate cellular differentiation in neuroinflammatory disease. These extensive studies have been reviewed elsewhere; consensus exists in the finding that the vast majority of CD437’s pro-apoptotic activities is mediated without direct interaction of the molecule with the receptor(s) it has initially been developed for, RARβ and RARγ, respectively. − …”

Regulation of Prolactin Receptor Levels and Activity in Breast Cancer

“…The action of retinoids was at the transcriptional level as there was no change in the stability of PRLr mRNA. Moreover, retinoic acid pre-treatment reduced PRLmediated STAT5 activation (59). In addition, treatment of MCF7 cells with aryl hydrocarbon (Ah) receptor agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in decrease in PRLr mRNA within 12h.…”