Polycystic ovary syndrome (PCOS) is a very common endocrine disorder characterized by chronic anovulation, clinical and/or biochemical hyperandrogenism, and/or polycystic ovaries. But most experts consider that hyperandrogenism is the main characteristic of PCOS. Several theories propose different mechanisms to explain PCOS manifestations: (1) a primary enzymatic default in the ovarian and/or adrenal steroidogenesis; (2) an impairment in gonadotropin releasing hormone (GnRH) secretion that promotes luteal hormone (LH) secretion; or (3) alterations in insulin actions that lead to insulin resistance with compensatory hyperinsulinemia. However, in the past 20 years there has been growing evidence supporting that defects in insulin actions or in the insulin signalling pathways are central in the pathogenesis of the syndrome. Indeed, most women with PCOS are metabolically insulin resistant, in part due to genetic predisposition and in part secondary to obesity. But some women with typical PCOS do not display insulin resistance, which supports the hypothesis of a genetic predisposition specific to PCOS that would be revealed by the development of insulin resistance and compensatory hyperinsulinemia in most, but not all, women with PCOS. However, these hypotheses are not yet appropriately confirmed, and more research is still needed to unravel the true pathogenesis underlying this syndrome. The present review thus aims at discussing new concepts and findings regarding insulin actions in PCOS women and how it is related to hyperandrogenemia.

Following removal of the primary breast tumour by conservative surgery, patients may still have additional malignant foci scattered throughout the breast. Radiation treatments are not designed to eliminate all these residual cancer cells. Rather, the radiation dose is calculated to optimise long-term results with minimal complications. In a tumour, cancer cells are surrounded by a basement membrane, which plays an important role in the regulation of gene expression. Using an invasion chamber, we have shown that irradiation before cell plating of a reconstituted basement membrane (Matrigel; Becton Dickinson, Bedford, MA, USA) increased the invasiveness of the breast cancer cells MDA-MB-231. This radiation enhancement of invasion was associated with the upregulation of the pro-invasive gene matrix metalloproteinase (MMP)-2. The expression of membrane type 1 matrix metalloproteinase (MT1-MMP) and tissue inhibitor of metalloproteinase-2 (TIMP), which are required to activate the MMP-2, were also increased. Confirming the role of MMP-2 and MT1-MMP, radiation enhancement of cancer cell invasion was prevented by an MMP-2 inhibitor and an anti-MT1-MMP antibody. This study also demonstrated that radiation can potentially enhance the invasion ability by inducing the release of pro-invasive factors stored in the Matrigel. Conversely, no enhancement of invasiveness was observed with the low metastatic cell line MCF-7. This lack of invasiveness correlated with the absence of the MMP-2 activator MT1-MMP in the MCF-7 cells. Radiotherapy is an efficient modality to treat breast cancer which could be further improved by inhibiting the pro-invasive gene upregulated by radiation.

In malignant breast cancer, estrogen metabolism is altered, favoring the accumulation of hydroxyestradiols, which can generate free radicals. These reactive species can activate matrix metalloproteinases (MMPs), which in turn can hydrolyze the proteins of the extracellular matrix (ECM) that act as a barrier to tumor cell passage. The aim of this study was to determine whether reactive oxygen species generated by 4-hydroxyestradiol (4-OHE 2 ) can activate MMP-2 and then enhance the invasiveness of breast cancer cells MDA-MB-231 in vitro. Invasion and metastases development require the degradation of the extracellular matrix (ECM), which acts as a barrier to tumor cell passage. ECM consists of interstitial matrix and basement membrane (BM). The first step of tumor invasion is characterized by the degradation of BM components, particularly type IV collagen, laminin and proteoglycan. 1 Cancer cells can then migrate through the interstitial matrix by breaking down its protein components and then either entering the lymphatic capillaries or migrating a second time through BM to reach the blood stream.ECM proteins can be degraded by proteases, mainly the matrix metalloproteinases (MMPs). 2,3 In breast cancer, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9 and MMP-13 are frequently detected; however, their respective importance for breast cancer progression still needs to be investigated. 4 -6 Nevertheless, the expression of MMP-2 has been linked to invasiveness of breast carcinoma cells, and its detection in breast carcinoma tissue was associated with a shortened recurrence-free survival. 7,8 MMPs are released under an inactive form (proMMPs) by cancer cells, but also by the stroma, i.e., fibroblast and endothelial cells. 9,10 Under their inactive proMMP forms, the propeptide domain covers the active site blocking access to substrate. This configuration is stabilized through the interaction between a cysteine located at a key position in the propeptide and a zinc atom at the MMP active site. 11,12 Expression and activation of proMMPs are considered to be important steps in metastases development. 2 It is proposed that proMMP-2 activation involves the cleavage of its propeptide by a membrane type 1-matrix metalloproteinase (MT1-MMP) molecule located on cell surfaces. ProMMP-2 binds to MT1-MMP using TIMP-2 as an adaptor by forming a trimolecular complex on the cell surface. 13 In this complex, the N-terminal domain of the tissue-inhibitor of matrix metalloproteinase 2 (TIMP-2) binds the catalytic domain of MT1-MMP and its C-terminal domain binds the hemopexin-like domain of proMMP-2. Another MT1-MMP near the complex cleaves the propeptide bond of proMMP-2 and generates an intermediate form, which is then converted into a fully active enzyme by an autoproteolytic mechanism. Consequently, active MMP-2 is then located directly at the migration front. 13,14 On the other hand, TIMP-2 plays a dual role since it can also inhibit MMP-2 by forming noncovalent associations with the active site of the MMP-2.ProMMP activation can also be achiev...

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