Retinoic acid induces expression of the interleukin‐1β gene in cultured normal human mammary epithelial cells and in human breast carcinoma lines

Abstract

Retinoic acid (RA) and its derivatives inhibit the proliferation of normal human mammary epithelial cells (HMEC) and some breast carcinoma lines by mechanisms which are not fully understood. To identify genes that mediate RA-induced cell growth arrest, an HMEC cDNA library was synthesized and subtractive screening was performed. We identified the interleukin-1beta (IL-1beta) gene as an RA induced gene in HMEC. Northern blot analyses showed that the IL-1beta gene was up-regulated as early as 2 h after RA treatment. Results from the treatment of HMEC with cycloheximide and actinomycin D indicated that the regulation of the IL-1beta gene by RA occurred at the transcriptional level and that the IL-1beta gene is a direct, downstream target gene of RA. To evaluate the effects of IL-1beta on cell proliferation, the proliferation of HMEC was measured in the presence of RA or IL-1beta, or both. Either RA or IL-1beta could significantly inhibit the proliferation of HMEC. However, the addition of soluble IL-1 receptor antagonist (sIL-1ra) to the cell culture medium did not block RA-induced HMEC growth inhibition, whereas sIL-1ra did block the growth inhibition of HMEC by IL-1beta. IL-1beta expression was not observed in the three carcinoma cell lines, MCF-7, MDA-MB-231, and MDA-MB-468, as compared to the HMEC. Growth curves of the breast carcinoma cell lines showed strong inhibitory effects of RA and IL-1beta on the growth of the estrogen receptor (ER) positive MCF-7 cell line, but only a small effect on the ER negative MDA-MB-231 cells. The expression of the IL-1beta gene was also transcriptionally activated by RA in normal epithelial cells of prostate and oral cavity. Our results suggest that: (a) the IL-1beta gene is a primary target of RA receptors in HMEC; (b) the enhanced expression of the IL-1beta gene does not mediate the RA-induced growth arrest of HMEC; and (c) the expression of the IL-1beta gene is low or absent in all three human breast carcinoma cell lines examined, but the defect in the IL-1beta signaling pathway may be different in ER positive versus ER negative carcinoma cells.

Retinoid pathway and cancer therapeutics

“…Tamoxifen and fenretinide combination therapy is an active treatment regimen in metastatic breast cancer patients, but not in estrogen receptor negative metastatic breast cancer or in patients whose disease had progressed after tamoxifen treatment [185]. Retinoids do not require estrogen receptors for their actions; they may affect neoplastic transformation in estrogen-negative cells, in contrast to tamoxifen, whose primary mechanism of action is through estrogen receptors [186, 187]. In spite of this, retinoids and rexinoids seem to be more active in estrogen-positive than in estrogen-negative precancerous tissue [188].…”

Osteoprotegrin and the bone homing and colonization potential of breast cancer cells

“…Since 231 cells do not produce IL-1b [Liu and Gudas, 2002] and IL-1b is a metastasisinducing cytokine [Hoosein, 1998] that has effects on OPG in other cell systems [Penno et al, 2002], on growth of cancer cells [Hoosein, 1998] and on metastasis to bone marrow [Hoosein, 1998], we examined the effects of IL1b on OPG production by these breast cancer cells and differences, if any, in OPG induction by IL-1b in metastasis capable and suppressed cells.…”

IL‐1 family in breast cancer: Potential interplay with leptin and other adipocytokines

“…Normal human mammary epithelial cells (HMEC) express the receptors for IL-1 family members since IL-1b inhibits significantly the proliferation of HMECs and IL-1ra blocks this growth inhibition [36]. Both expression and distribution of IL-1 family members have been well studied in human mammary cancer tissue where they regulate tumour activity within the microenvironment surrounding breast tumour [37][38][39].…”

“…In contrast, genes of IL-1 a , IL-1b, and IL-1ra are preferentially expressed in highly malignant and invasive mammary cell lines (BT 20, BT 549, HS 578T, and MDA-MB 231) and are not detected in other cell lines tested (MCF-7, T47-D, ZR75-1, and SKBR-3) [10]. In one study, however, the authors found no IL-1b expression in the three breast cancer cell lines MCF-7, MDA-MB231 and MDA-MB468 [36]. Collectively, this body of work suggests an autocrine/paracrine functional IL-1 system in the model of breast cancer.…”