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There is limited published literature on the risk of breast cancer in transgender patients. We report a case of an aggressive triple negative inflammatory breast cancer in a male-to-female transsexual. This patient had a complicated psychiatric history with significant antipsychotic use, and the case raises several questions about the pathogenesis of this breast cancer. The literature on breast cancer in transgender patients and in relation to hyperprolactinaemia is reviewed.

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The aim of this study was to gain information relevant to disc repair processes. Limited degradation of the collagen matrix by matrix metalloproteases (MMPs) may facilitate the loosening of cell-cell and cell-matrix interactions within the injured intervertebral disc (IVD) to favour the penetration of blood vessels and migration of fibroblasts into the defect to promote repair processes. Gelatinase A (MMP-2) has a particularly important role to play in angiogenesis, in the present study we investigated the in vitro regulation of MMP-2 by Transforming Growth Factor-beta 1 (TGF-beta 1) and Insulin-like Growth Factor-1 (beta IGF-I) in cells from the nucleus pulposus (NP) of the ovine IVD. Ovine NP cells were grown in alginate bead cultures in complete medium (10% foetal calf serum) for 7 days, established in serum-free conditions for 24 h, then stimulated with TGF-beta 1 (0.1 or 10 ng/ml) or IGF-I (2 or 50 ng/ml) +/-Concanavalin A (20 microg/ml) for an additional 48 h. Conditioned medium was examined for matrix metalloproteases using gelatin zymography, Tissue Inhibitor of Metalloproteinase 2 (TIMP-2) and Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) were immunolocalised in beads. Pro (72 kDa) and active (59 kDa) MMP-2 were the major gelatinolytic MMPs detected in control cultures, the TGF-beta 1 and IGF-I treatments significantly decreased levels of the active MMP-2, inclusion of Concanavalin A resulted in a complete reversal of this trend with IGF-I, and to a lesser extent with TGF-beta 1. Cell surface levels of TIMP-2 and MT1-MMP were decreased by the TGF-beta 1 treatment while IGF-I only appeared to decrease TIMP-2 expression. The findings of this study provide some insight as to why dense avascular connective tissues such as the intervertebral disc have such a poor healing potential.

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The growth regulatory activity of the insulin-like growth factor binding proteins (IGFBPs) may be modulated by post-translational modifications such as glycosylation, limited proteolysis and phosphorylation. In this study, we have examined phosphorylation of IGFBP-3 in two breast cancer cell lines: the estrogen receptor negative (ER-ve) Hs578T cell line in which IGFBP-3 is normally expressed, and ER+ve T47D breast cancer cells transfected with IGFBP-3 cDNA (T47D(BP-3)) and therefore expressing IGFBP-3 constitutively. Metabolic labelling with [32P] orthophosphate revealed that both cell lines secreted phosphorylated IGFBP-3 similar in size to plasma IGFBP-3 phosphorylated in vitro with casein kinase II, and that IGFBP-3 phosphorylation was differentially modulated in the two cell lines. In Hs578T cells, retinoic acid (10-100 nM) increased IGFBP-3 phosphorylation to a maximum of 150% of control. IGF-I, but not [LR3]IGF-I, reduced the proportion of phosphorylated IGFBP-3 in Hs578T conditioned medium, consistent with increased release of non-phosphorylated, cell-associated IGFBP-3. By contrast, IGFBP-3 phosphorylation in T47D(BP-3) cells was not affected by retinoic acid or IGF-I, but appeared slightly increased by estradiol. Together these data indicate that phosphorylation of IGFBP-3 in breast cancer cells may be regulated by agents known to affect breast cancer cell proliferation.

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The insulin-like growth factors (IGFs) stimulate the proliferation of human breast cancer cells, including the estrogen-dependent cell line MCF-7. These cells secrete regulatory IGF-binding proteins (IGFBPs) which may enhance or attenuate IGF-stimulated cell proliferation. In this study, we have used RIA to quantify the production and regulation of IGFBP-3 and IGFBP-6 by MCF-7 cells in vitro. Under basal (serum- and phenol red-free) conditions, IGFBP-3 and IGFBP-6 accumulated in 72 h-conditioned MCF-7 medium to concentrations of approximately 0.18 nM and 0.02 nM, respectively. Treatment with retinoic acid (RA, 100 nM) increased medium concentrations of IGFBP-3 to 175 +/- 8% (mean +/- SE, n = 4), and IGFBP-6 to 217 +/- 20% of control values. Forskolin (0.5 microM) or dibutyryl cAMP (db-cAMP, 1 mM) increased both proteins 2- to 3-fold. In the presence of 100 nM RA, the stimulation elicited by these agents was enhanced, with IGFBP-3 levels increasing to 6-fold above that seen with RA alone. IGFBP-6 increased 12-fold with RA + forskolin and 20-fold with RA + dbcAMP. Estrogen (10 nM estradiol) reduced basal IGFBP-3 levels by 25% but increased IGFBP-6 1.5- to 2-fold. The stimulatory effect of RA + forskolin on IGFBP-3 was partially reversed by estrogen, whereas RA + forskolin-stimulated IGFBP-6 levels were further increased by estrogen. Increased IGFBP-3 and -6 production in response to RA + forskolin was accompanied by a decrease in IGF-stimulated thymidine incorporation into DNA; by contrast, the bioactivity of an IGF analog that does not bind with IGFBPs, [Gln3, Ala4, Tyr15, Leu16]IGF-I, was unchanged under these conditions. These data demonstrate that modulating the production of IGFBPs can lead to changes in the sensitivity of breast cancer cells to IGFs, and as a result change the cell proliferative effects of these growth factors. Further, IGFBP-3 and IGFBP-6 are differentially regulated by estrogen. Dissecting the roles of the individual IGFBPs is essential to understanding how such differential regulation will ultimately affect IGF-stimulated cell proliferation in breast cancer.

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