Interleukin‐3: A putative protective factor against breast cancer which is secreted by male but not female breast fibroblasts

Abstract

The enzyme 17 beta-hydroxysteroid dehydrogenase (17-HSD) is a key regulator of intracellular 17 beta-estradiol (E2), which is associated with breast cancer and is influenced by paracrine factors released by breast-cancer fibroblasts. Since the incidence of breast cancer is much higher in females than in males, we have used an in vitro cell culture system to investigate whether male fibroblasts may inhibit breast-cancer genesis by restricting the intracellular accumulation of E2. Fibroblasts were obtained from normal males and females undergoing reduction mammoplasty, and from females with benign or malignant breast lesions. Fibroblast-conditioned medium (CM) was incubated with the established breast-cancer cell line, MCF-7, and its effects on 17-HSD activity were assessed. CM (25% v/v) from male breast fibroblasts had a significant inhibitory effect on reductive 17-HSD, decreasing E2 production. This was in direct contrast to the effects of CM from female breast fibroblasts, which had a powerful stimulatory effect on reductive 17-HSD. RT-PCR allowing simultaneous detection of a range of cytokines was performed on each type of fibroblast. IL-3 mRNA was consistently detected in fibroblasts from male but not female breast tissue. Addition of rhIL-3 to cultures of MCF-7 caused a reduction in 17-HSD activity and addition of a polyclonal antibody directed against IL-3 to male CM completely reversed the inhibitory effects of CM. Thus, male breast fibroblasts may be responsible for secreting IL-3-like factors which, given the considerably lower incidence rates of breast cancer in men, may have a protective effect against breast cancer.

Interleukin 3 and schizophrenia: the impact of sex and family history

“…Furthermore, our finding of sex-specific associations in this region has strong genomic and molecular basis, that is, the existence of EREs and other coordinating transcription factor binding sites in this region and the report of sex-specific expression of IL3 and ACSL6 genes. 34,35 We also find that FH is a contributing factor for the associations. Consistent associations are observed only in those subjects with a positive FH of schizophrenia.…”

“…In one report, sex-specific expression of IL3 was found in breast cancer patients. 34 In another report, sexually dimorphic expression of both ACSL6 and IL3 was reported in a mouse model. 35 In addition, the key SNPs defining all risk haplotypes observed in all three samples are potentially functional.…”

Expression of cytokine messenger RNA in normal and neoplastic human breast tissue: Identification of interleukin-8 as a potential regulatory factor in breast tumours

“…Amplification was carried out using a thermal cycler (Hybaid OmniGene, London, UK) with an initial denaturation step of 94°C for 2 min followed by 35 cycles of 94°C for 30 sec, 55°C for 30 sec and 72°C for 30 sec and concluded by a primer extension temperature of 72°C for 5 min. Amplification of IL-3 mRNA used similar cycling except for the annealing temperature which was 62°C (Speirs et al, 1995). PCR products were electrophoresed through a 1% w/v agarose gel and visualised by ethidium bromide (Sigma) staining under UV light.…”

“…Cytokines, in particular, play a key role in breast carcinogenesis and subsequent proliferative behaviour. These factors are secreted by many cell types including those of the breast, e.g., interleukin (IL)-1␤ (Duncan et al, 1994), IL-3 (Speirs et al, 1995), IL-6 (Adams et al, 1991) and tumor necrosis factor-␣ (TNF-␣) (Bebók et al, 1994), where they have pleiotrophic actions. Paracrine effects of cytokines, particularly IL-6, have been demonstrated in vitro; incubation of breast cancer cell lines with conditioned medium (CM) derived from fibroblasts results in growth promoter/inhibitor effects (Adams et al, 1991;van Roozendaal et al, 1992;Ryan et al, 1993;Speirs et al, 1995).…”

Cytokines, Neovascularization and Breast Cancer

“…growth factors and angiogenesis factors). Virtually all nucleated cells including breast cells, can be induced to express cytokines e.g., tumor necrosis factor (TNF) [35], interleukin (IL)1 [36], IL3 [37], and IL6 [38,39]. Recently, the cytokine IL8 has been …”