Joëlle Desreux

Restricted expression of membrane type 1-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells.

The membrane type‐1 matrix metalloproteinase (MT1‐MMP), a protease originally identified in breast carcinoma, is characterized by its capacity to activate other MMPs (MMP‐2 and MMP‐13) and to degrade extracellular matrix. Our study was undertaken to localize and identify the MT1‐MMP expressing cells in human breast adenocarcinomas. A textural analysis of images obtained by immunohistochemistry and in situ hybridization showed precisely the co‐expression of alpha smooth muscle actin (αSM actin) and MT1‐MMP in myofibroblasts. MT1‐MMP expression is confined to myofibroblasts in close contact with tumor cells. In sharp contrast, the expression of MMP‐2 was more widely distributed in both αSM actin positive and negative cells close to and at distance from cancer cell clusters. Our in vitro observations are consistent with the higher level of MT1‐MMP expression and of MMP‐2 activation observed in αSM actin positive fibroblasts derived from breast tumors, as compared to normal breast fibroblasts. Collectively, these results implicate myofibroblasts as major producer of MT1‐MMP in breast cancer and emphasize the importance of stromal‐epithelial cell interactions in their progression.

Hormone therapy and breast cancer risk

Hormone therapy (HT) is the most efficacious intervention for the relief of climacteric symptoms. Controversies surrounding HT have left many women puzzled and afraid. Gynecologists are faced with long-standing beneficial assumptions challenged by an abundance of robust detrimental new data, with little guidance on how to interpret these findings. Prescriptions for HT (and incidence of breast cancers in some areas) have fallen over the last 3 years due to anxiety provoked about breast cancer risk and recurrence. The current ‘clinical climate’ is against HT. Due to a lack of effective alternatives, women suffering from estrogen-deficiency symptoms are still requesting objective information about HT, particularly those at higher risk of breast cancer or those with a past history of breast cancer. In this situation, discussion of the current clinical uncertainty surrounding the use of HT must be undertaken to ensure that women are adequately informed. The objective of this presentation is to provide a framework for understanding breast cancer risk associated with HT. What are the precise molecular mechanisms of estrogen and progestin in the initiation of breast cancer? Does the risk of estrogen-only therapy on breast cancer vary by dose, constituent, route and duration of administration and cessation of use? Does HT, in addition to increasing risk for breast cancer, affect the type of breast cancer (lobular and ductal) diagnosed? Is HT associated with breast cancers that have better prognostic factors? How relevant are the changes in mammographic breast density associated with HT for the evaluation of breast cancer risk? What is the additional global health risk/benefit ratio associated with the selective use of progesterone or progestin that may confer a significant cardiovascular benefit, such as drospirenone? It is currently assumed and tested that new hormones with particular pharmacological profiles may ultimately achieve their therapeutic goal of relieving climacteric symptoms without an associated moderate increased risk of breast cancer.

EMAS position statement: Individualized breast cancer screening versus population-based mammography screening programmes

INTRODUCTION Breast cancer is the most prevalent cancer in women, with slightly more than ten percent developing the disease in Western countries. Mammography screening is a well established method to detect breast cancer. AIMS The aim of the position statement is to review critically the advantages and shortcomings of population based mammography screening. MATERIALS AND METHODS Literature review and consensus of expert opinion. RESULTS AND CONCLUSION Mammography screening programmes vary worldwide. Thus there are differences in the age at which screening is started and stopped and in the screening interval. Furthermore differences in screening quality (such as equipment, technique, resolution, single or double reading, recall rates) result in a sensitivity varying from 70% to 94% between studies. Reporting results of screening is subject to different types of bias such as overdiagnosis. Thus because of the limitations of population-based mammography screening programmes an algorithm for individualized screening is proposed.

Effects of a progestogen on normal human breast epithelial cell apoptosis in vitro and in vivo

Many investigators have reported cyclic proliferation of normal human breast epithelial cells. A delicate balance between proliferation and apoptosis (programmed cell death) ensures breast homeostasis. Both the follicular and luteal phases of the menstrual cycle are characterized by proliferation, whereas apoptosis occurs only at the end of the latter phase. In this study, we observed that the withdrawal of a synthetic progestin (nomegestrol acetate or NOMAC), but not continuous treatment with it, induced apoptosis of normal human breast epithelial cells in vitro and in women who applied NOMAC gel to their breasts. Furthermore, this apoptotic response was specific to normal breast cells, since withdrawal of NOMAC did not induce apoptosis of tumoral T47D cells in vitro or of fibroadenoma cells in women. These observations open up new perspectives in the prevention of hyperplasia and breast cancer.

Progesterone Receptor Activation. An Alternative to SERMs in Breast Cancer

Data regarding the effects of progesterone and a progestagen on human normal breast epithelial cell proliferation and apoptosis are presented here. In postmenopausal women, adding progesterone to percutaneously administrated oestradiol significantly reduces the proliferation induced by oestradiol. In vitro and in premenopausal women, stopping the administration of nomegestrol acetate triggers a peak of apoptosis. Fibro-adenoma and cancerous cells do not show this regulation of apoptosis. Progesterone seems to be important in normal breast homeostasis.

Should we individualize breast cancer screening

Publicly organized population breast cancer screening is presently hotly debated. Indeed, population screening is poorly effective, induces harms in a healthy population and is costly. However, stopping all kind of screening of low- and average-risk women would be problematic as about 70% of breast cancers are diagnosed in those subgroups, and maintaining current population screening in high-risk women would be insufficient. We propose herein a review about the advantages and the inconvenience of individualized screening. The latter could be a more efficient strategy. The principles of individualized screening are (a) to start from the age at which the breast cancer risk is equal to that for an average women aged 50 years, (b) to stop when the risk of co-mortality exceeds the risk of breast cancer mortality, (c) to adapt the exams frequency and the imaging modalities to the individual risk and to the breast density, (d) to reassess regularly and individually the screening strategy, and (e) to discuss honestly with each woman in order to help her to decide if she participates or not.

Effects of Tibolone on Sulfatase Pathway of Estrogens Metabolism and on Growth of MCF-7 Human Breast Tumors Implanted in Ovariectomized Nude Mice

Background: The benefits of estrogen plus progestin in healthy post-menopausal women remain uncertain. Tibolone, with its in vitro documented inhibitory effects on estrogens metabolism and its selective action on breast, may be an alternative that could favorably influence the health benefit of hormone replacement therapy. Methods: We studied the effect of tibolone on the tumor growth of MCF-7 cells implanted in 40 ovariectomized nude mice, receiving subcutaneous pellets of 17β-estradiol, estrone, estrone-sulfate or vehicle, and daily gavages of tibolone or placebo. Results: Tibolone, although used at high dose, did not stimulate nor inhibit the estrogen-induced tumors, nor the tumors in estrogen-deprived mice. Measurements of plasma levels of estrogens indicated that tibolone potently stimulated sulfotransferase activity, but intra-tumor levels of estrogens were not significantly modified by tibolone. Conclusions: This in vivo study performed with high dose of orally administered tibolone that allowed its hepatic conversion into active metabolites has shown no significant effect on breast tumors growth. Tibolone increased the circulating sulfated estrogens by its activity on the hepatic sulfation but not the intra-tumor levels of estrogens (free or sulfated). However, further studies of dose-response curve and molecular markers are needed to exclude definitely a stimulatory effect of tibolone on tumor growth.

2 STRIPINESS OF MAMMOGRAMS: A NEW TOOL FOR INDIVIDUAL EVALUATION OF HRT EFFECTS ON BREASTS? A PRELIMINARY STUDY

The decision of when to begin and what type of osteoporosis treatment to use should be based on the individual need and taking into account other major risks for each individual case: hepatic and renal function, drug allergies, comorbidities, previous treatments, contraindications, secondary effects of the drugs and cost. Osteoporosis, as a chronic disease, requires the use of individualized methods and sequential treatments. In theory, initial treatments would be the use of drugs aimed at the physiopathology of the rapid loss of bone mass during the first years of menopause, which is produced by the increase in secondary bone resorption and the decrease in estrogens. The most appropriate drugs are HRT in symptomatic women and SERMs in asymptomatic ones. The ideal pharmacological SERM profile is an attractive challenge and, after the negative results of the WHI, we would say a necessity. Other possibilities would be HRT for two or three years, and SERMs afterwards (if there are no menopausal symptoms), or the combination of an estrogen with a SERM (TSEC) (if there are any). Later on, there is a period of increased resorption and diminished bone formation, coinciding with more than ten years of menopause and with a greater risk for hip fracture, where drugs such as the bisphosphonates, strontium ranelate or denosumab have shown their effectiveness. Finally, and now in women over 70-75 years of age, there is an important decrease in bone formation (where in cases of very high risk for fracture PTH might be indicated).