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After years of studying cardiovascular diseases (CVD) in men due to their higher incidence compared to women, attention is now being paid to female CVD and their pathophysiology. Even though premenopausal women have a lower incidence of CVD, this disparity progressively diminishes after menopause, highlighting the key role of sex hormones. Many preclinical and fundamental studies have demonstrated protective effects of estrogens on arterial endothelium, suggesting that hormone therapy could improve cardiovascular health in menopausal women. However, disappointing outcomes from a major clinical trial two decades ago questioned the cardiovascular protection by estrogens with age. In this review, we will summarize the main clinical and experimental studies reporting the effects of estrogens on CVD, with a focus on their impact on endothelial function. Then, we will present abnormalities in the expression and signaling of estrogen receptors (ERs) in the arteries, and the contribution of conventional estrogens to arterial protection during aging. Finally, we will examine how recent advances in the mechanisms of action of ERa could help to optimize hormone therapy for menopause., (© 2024 médecine/sciences – Inserm.)

Background: Despite the advancement in therapy, breast cancer still remains the most common malignancy in women globally due in part to its heterogeneity. Triple-negative breast cancer (TNBC) represents up to 20% of all breast cancer variants, an aggressive disease with poorer outcomes compared to other breast cancer subtypes. No targeted therapies are currently approved for TNBC, and newer treatment approaches are seriously needed. Androgen receptor (AR), another hormonal receptor, is often expressed in breast cancer, and its role depends on the relative levels of circulating estrogens and androgens. This study aimed to assess the expression of AR in breast cancer in a tertiary hospital in Ghana., Methodology: Immunohistochemical staining for AR was performed on tissue microarray (TMA) blocks, of which estrogen receptor, progesterone receptor, and Her-2/neu had already been done. 197 cases were suitable for the study. Results from the immunostaining were analyzed using the SPSS version 23 for descriptive statistics and correlations (χ2 and Pearson tests)., Results: 197 TMA cases were used. TNBCs constitute 61.9% of the cancers. The majority of these tumors were grade III, ductal carcinoma NST. The mean age was 49.86 ± 14.09, and the modal age group was 40-49 years. Our cases showed 23% AR expression in triple-negative cancers. The study also established that AR is more frequently expressed in low-grade tumors compared to high-grade ones., Conclusion: There is an appreciable level of AR expression in our cases; however, most are quadruple negative. However, AR is more frequently expressed in low-grade tumors than high-grade ones., (Copyright © 2024 Copyright: © 2024 Annals of African Medicine.)

Synchronous bilateral breast cancers (SBBC) are characterized by extensive clinical and morphological heterogeneity, with an frequency between 1.5 and 3.2%. Women treated for unilateral breast cancer are at higher risk of developing contralateral breast cancer. Screening and advances in breast imaging have improved detection rates of SBBC. Our study aims to analyze the epidemiological, clinical, histological and therapeutic features of bilateral breast cancer. We conducted a cross-sectional study of patients with breast cancer treated at the Mohammed VI Center over a two year period. Statistical analysis of the results was performed using R. software. 31 patients had SBBC, representing 2.4% of breast cancer cases in our Center. The average age was 47.8 ± 8.4 years, 22.6% of patients used oral contraceptives. A family history of breast cancer was observed in 22.6% of cases. The most common histological type was invasive ductal carcinoma (58.1%), SBR grade II and III were common (38.7%). Hormone receptors were positive for progesterone (38.7%) and for estrogen (41.9%). HER2 was overexpressed in 20.0% of cases. 29.0% of patients received hormonal therapy and 3.2% targeted therapies. Our study showed that bilateral breast cancer represents a small percentage of all breast cancers but have specific clinical features that help to differentiate it from unilateral breast cancer., Competing Interests: Les auteurs ne déclarent aucun conflit d'intérêt.

The prognosis of infracentimetric breast cancers (BC) is heterogeneous. The EURISTIC survey describes how French oncology specialists perceive the prognosis of pT1a,b pN0 BCs. A self-administered questionnaire has been sent to over 2000 French BC specialists. Six hundred and sixty-three physicians responded. Fifty-eight percent do not consider tumor size as a key prognostic criterion. They consider that the cutoff for poor prognosis is 22mm, 10mm and 7mm for hormone receptors (HRs)+, HER2+ and triple-negative (TN) tumors respectively. Eighty-three percent of respondents consider that a HR+ pT1a,b tumor has a good prognosis (21% and 8% for HER2+ and TN respectively). Factors perceived as most detrimental are: HER2 overexpression (29% of respondents); HR- (20%); high grade (20%); TN status (14%); high KI67 (5%); presence of lymphovascular invasion (3%); young age (2%) and high mitotic index (1%). For French specialists, immunohistochemical characteristics, in particular hormone and HER2 status, are strong prognostic factors in BCs below 1cm., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Endocrine therapy is a compulsory step in the adjuvant management of early breast cancer expressing the estrogen receptor, by reducing as much as possible serum and tissue levels of estrogens. Tamoxifen is the standard therapy for non-menopausal women. Ovarian function suppression, in addition to exemestane or tamoxifen, could be an alternative option for young women at high risk of recurrence and non menopausal after adjuvant or neo-adjuvant chemotherapy. Recent studies show a trend for improvement of overall survival and disease-free-survival with aromatase inhibitors among postmenopausal women. However, safety of aromatase inhibitors is controversial and adverse events may lead to switch for tamoxifen with no loss of efficacy. Extension therapy by tamoxifen or aromatase inhibitor after five years of tamoxifen and for a total duration of ten years significantly improves overall survival. There is to date no data supporting the extension therapy after five years of aromatase inhibitor., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Discordances between hormone receptors and HER2 status in primary and metastatic breast cancer have been reported by several studies. In this context, systematic biopsies could be clinically relevant in breast cancer to confirm the biological characteristics of a suspicious lesion. In this article, illustrated by 2 case reports and based on a recent review on this topic, we discuss the clinical significance of receptor discordances and possible diagnosis of a secondary primary tumor. The role of these biopsies for the identification of new therapeutic targets is also envisaged as well as underlying mechanisms for receptors' modification like tumoral heterogeneity, clonal selection and technical artifacts.

Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients., (Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.)

Luminal breast cancers (i.e. displaying œstrogen receptor expression) account for 70 to 80% of all breast cancers. It encompasses a heterogeneous population of tumors, differing by their clinical course, histopathological characteristics, phenotypes and molecular features. As a continuum of lesions, luminal breast tumors are critically challenged by the recent evolution in treatment decision making. Indeed, whilst about half of luminal breast cancers are associated with a very good prognosis (so-called luminal A tumors with regard to the intrinsic molecular classification), 20% of luminal tumors display a poor clinical outcome (i.e. luminal B tumors), the remaining tumors corresponding to intermediate lesions that are very difficult to accurately classify. Clearly, therapeutic issues are critical, since according to the vast majority of international consensus guidelines luminal A tumors are best treated by endocrine therapy, whilst an additional adjuvant chemotherapy will be proposed to patients harbouring luminal B breast cancer. By providing precise histopathological, phenotypic and molecular characterization of luminal breast tumors, the pathologist is actually the cornerstone of this therapeutic decision. Herein we aim to review the state-of-the-art knowledge on luminal breast carcinomas, with a perspective of routine clinical practice in 2015., (Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.)

Hormone receptors are expressed in more than 75% of breast cancer. Therefore, two prescription modalities of endocrine therapy could be proposed: either sequential or concomitant to breast cancer irradiation. If combined to radiotherapy, is endocrine therapy a radiosensitizer? Does endocrine therapy enhance the risk factor of radio-induced toxicity? Here, we will distinguish the interaction of ionizing radiation combined with therapies targeting oestrogen receptor (REα) from the interaction of ionizing radiation with oestrogen. This review aims at making clear all these items.

Osteogenesis imperfecta is an unusual disease also called Lobstein disease. Characterized by abnormalities of collagen biosynthesis, a possible mutation on 17th chromosome is described. On the other hand, 29% of breast cancers present a mutation on the same chromosome. Nevertheless, the association of osteogenesis imperfecta and breast cancer is at the moment unknown. Therapeutic management is very difficult because of a loss in dihydropyrimidine dehydrogenase for patients having osteogenesis imperfecta, generating some toxicity by default in catabolism of 5-fluorouracil. We report the case of a 49-year-old woman with a breast cancer in the context of osteogenesis imperfecta. Dosimetric considerations permitting to reduce chess dose level have been performed for this patient. With a follow-up of 6 months, no imaging fracture has been revealed after radiotherapy. No evident conclusion about radiation injury from a case report could be described in case of osteogenesis imperfecta. To our knowledge, this is the first case which take into account potential radiation induced toxicities., (Copyright © 2014. Published by Elsevier SAS.)

Purpose: Recent improvements in the detection of breast cancer at an early stage have resulted in a rising incidence of breast ductal carcinoma in situ with microinvasion. So far, there is no consensus regarding its optimal management. We hereby report on our 10-year single institutional experience in breast ductal carcinoma in situ with microinvasion including pathological reviewing., Patients and Methods: All consecutive patients treated for a ductal carcinoma in situ with microinvasion at the Institut Claudius-Regaud (Toulouse, France) over a 10-year period were included in this study. We reviewed all available histological materials., Results: Sixty-three patients were eligible for this study. Two patients presented with a lymph node invasion at diagnosis. Each patient benefited from initial surgical management, which consisted either in mastectomy (n=25) or conservative resection (n=37). Axillary exploration was performed in 52 patients (82%). After a median follow-up of 61.3 months [46.9;69], the 5-year overall survival and disease free survival were 98.2 (95% CI=[88.2;99.7]) and 89.5% (95% CI=[76.3;95.6]) respectively. Two delayed invasive relapses occurred leading to one specific death. The pathological review highlighted a trend towards a loss of HR and HER2 expression (9%) in the microinvasive component in comparison with its surrounded in situ carcinoma., Conclusion: The risk of initial lymph node involvement and delayed invasive local relapse deserve an optimal locoregional management including lymph node evaluation. The non-negligible discrepancy's rate between in situ and microinvasive components justifies HR status and HER2 expression assessment on the microinvasive component., (Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Triple-negative breast cancer (TNBC), as defined by the absence of estrogen and progesterone receptor expression, as well as the lack of HER2 overexpression/amplification, corresponds to 15% of breast cancer and represents an aggressive form of the disease. TNBC are frequently confounded with basal subtype in the molecular classification of breast cancer and also share some similarities with BRCA1-mutated tumors. Epidemiological and clinical characteristics are distinct from other subtypes, including a younger age at diagnosis, a higher risk of relapse in spite of increased chemosensitivity, and a higher incidence of lung and brain metastatic relapses. Conventional cytotoxics remain the mainstay of current systemic management but recent evaluation of more targeted therapeutics, including specific cytotoxics (such as the use of platinum salts), PARP and EGFR inhibition, and antiangiogenics have been performed, providing contrasted but rather disappointing results. Recent data indicate that TNBC represent a heterogeneous entity composed of multiple and distinct molecular subtypes, which should deserve specific targeted therapeutics.

Breast cancer remains a major public health problem. Even if there is an increase in this cancer curability, metastatic breast cancer remains a lethal disease in the vast majority of cases. Therapeutic advances in the chemotherapeutic and targeted therapies fields induced an increase in survival, however the proportion of long survivors remains low. Phenotypic instability, an early process initiated during tumour progression, and continued on the metastatic stage of the disease, can be one of the putative hypotheses explaining these results. An increasing amount of scientific data are pledging for a reanalysis of the phenotypic profile regarding hormone receptors and HER-2 status of metastatic lesions in order to identify drugable targets and allow individualisation of the treatment of these metastatic breast cancer patients. Phenotypic changes between the primary tumour and the paired metastatic lymph nodes are a challenging pitfall, raising the question of which site has to be assessed in the adjuvant treatment decision process. This article presents a comprehensive analysis of the frequency of theses phenotypic changes altogether with new modalities to evaluate this phenotypic status.

Apart from therapeutic advances related to new treatments, our practices in the management of early breast cancer have been modified by to key organizational settings (1) mass screening, substantially altering the presentation and epidemiology of breast cancer and (2) the development of guidelines to ensure that any patient management is in agreement with the demonstrated impact in the adjuvant treatment. In daily practice, the impact of screening and guidelines recommendations has put us now in a paradoxical situation: while the majority of non-metastatic breast cancers treated in the hexagon are node negative, most of the results of clinical studies on chemotherapy and targeted therapies today arise from populations predominantly node positive. Therefore, it seemed legitimate to convene a working group around a reflection on the directions of adjuvant chemotherapy in a growing node negative population in order to better respond to the questions of the field oncologists, trying to address the discrepancies between different existing guidelines.

During the past decade, molecular signatures allowed a better classification of breast carcinoma and a better evaluation of their prognosis. However, we still need predictive factors of treatment and /or prognosis factors specific of each patient. Regarding hormonal therapy, expression of hormone receptors is essential, but not sufficient to accurately predict response to treatment for all patients. To date, numerous data have identified different pathways of resistance to hormonal treatment, associated with heterogeneity in response to long term treatment. The challenge remains to identify and to anticipate these changes for each patient.

Even if prognosis of epithelial ovarian cancer remains very bad, survival and response to treatment are variable according to the patients. Determination of new prognostic markers helps us to adapt therapeutics for each patient and is necessary for the elaboration and the interpretation of clinical research studies. Many prognostic factors related to the tumor, the patient or the treatment, have been evaluated. The goal of this work is to review these parameters. So far, the most powerful variables are volume of residual disease after cytoreductive surgery, FIGO tumor stage, histologic type and grade of differentiation. The progress and accessibility to novel technologies applied to biology will make possible in the future the assessment of new prognostic profiles-based on genetic and/or proteomic tumor characteristics. The future also relies on the identification of predictive factors of response to treatment, but force is to note that on the last hundred publications testing predictive factors (p53, HER2, Topo-2-alpha, BRCA...), none have modified today our clinical practices.

We report the first case of malignant solitary fibrous tumor of the abdominal wall in a man. Immunohistochemical staining for CD34 and bcl-2 were positive. Surprisingly, estrogen and progesterone receptors were focally positive. Expression of steroid hormone receptor in solitary fibrous tumor was rarely reported in the literature. In a few series, these receptors were identified as a risk factor of recurrences after surgical excision. Six months after complete surgical resection of the mass, our patient has been quite well without any evidence of recurrence.

Androgens have a dual effect on mammary cells. Indeed, they have an influence on mammary cells proliferation thanks to several possible mechanisms, including their transformation into dihydrotestosterone (5alpha-reductase pathway) or into estradiol (aromatase pathway) or their binding to the androgen receptor (AR) and/or to the estrogen receptor (ER). Androgen signaling, using 5alpha-reductase pathway, enables the control of cell proliferation, mediated by AR. So androgen signaling plays a crucial role in breast homeostasis, negating the proliferative effects of estrogen signaling in the breast. When androgens transform into estrogens (aromatase pathway), they increase cell proliferation and mammary carcinogenesis risk. High levels of androgens and estrogens in the serum are associated with increased incidence of postmenopausal breast cancers. Genetic variations in metabolic genes (CYP11, CYP19) and in the AR gene are both involved in dual effects of androgens. Since mammary cells metabolic enzymes vary with time, aging increases the risk of breast cancer induced by estrogens and androgens. In addition, AR function can be perturbed by low doses of synthetic progestin, acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. In the future, the determination of AR expression in infiltrative breast cancer specimens and circulating androgens levels could provide additional information about hormonal dependency and prognosis of breast carcinomas.

Introduction: The incidence of lung cancer is increasing dramatically in women in France. It is now the leading cause of cancer deaths among women in the USA and the second in France., State of the Art: Lung cancer occurring in women displays some specific epidemiological, radiological, clinical and pathological characteristics. Moreover, both prognosis and response to treatment appear to be different from men. In line with these findings, lung carcinogenesis is, at least in part, distinct in women and involves different mechanisms and signalling pathways. We emphasize in this review genetic and hormonal specificities based upon epidemiological and biological studies. Moreover, we focus on lung cancer developing during pregnancy by reporting an individual case and discussing the published literature., Perspectives and Conclusions: Recent works suggest that lung cancer in women is a distinct entity with specific carcinogenesis. We propose that a better knowledge of this entity will permit the identification of specific genetic alterations or hormonal profiles that may serve as new therapeutic targets.

Background: We report a case of multiple benign nodular hidradenomas associated with malignant nodular hidradenoma in a hypogonadic patient., Case-Report: A 49 year-old man presented 11 benign nodular hidradenomas in the pectoral region. A malignant nodular hidradenoma had recently appeared in this region some distance from the pre-existing benign modular hidradenomas. This patient had peripheral hypogonadism associated with congenital bilateral cryptorchidia responsible for gynecomastia due to "relative hyperestrogenism". Large numbers of estrogen receptors were demonstrated in each of the benign nodular hidradenomas. The malignant nodular hidradenoma mass was unavailable and screening for these receptors was not possible., Discussion: Cases of multiple nodular hidradenoma are extremely rare: we have seen only two. To the best of our knowledge, there have been no reports to date of combined malignant nodular hidradenoma and multiple benign nodular hidradenoma. However, there is histological evidence of transition forms. The coexistence of endocrine anomalies associated with this type of tumour has never been reported. However, the presence of estrogen receptors has occasionally been demonstrated in benign nodular hidradenomas. Our patient's endocrine disease may have played a role in the presentation of multiple hidradenomas, but this cannot be demonstrated.

After a dominant role for more than 30 years, tamoxifen has been progressively replaced by aromatase inhibitors as adjuvant treatment for breast cancer in the menopaused woman. We present here a recall of the mechanisms of action involved together with a review of clinical trials leading to the current situation. Giving trial results in detail, we discuss the current evidence as well as open questions. The populations concerned and trial methodologies are analyzed. Comparative tolerance is detailed. Several questions remain open, either due to the lack of evidence to be obtained from ongoing trials or sufficient follow-up. The evidence presented is commented in light of the American (ASCO) and European (Saint-Gallen) or French (Saint-Paul) guidelines.

The histological changes underwent by endometrium during a natural menstrual cycle were described more than 50 years ago. Dating yields several methodological flaws, with intra- and inter-observer variability and shows questionable relationship to endometrial receptivity. The best studied endometrial factors involved in implantation include the formation of luminal epithelial "pinopodes", expression of adhesion molecules and of cytokines. Ovarian stimulation for IVF is known to affect luteal phase function. Factors influencing the endometrial receptivity in such cycles are poorly understood. Studies comparing the endometrium in IVF cycles with natural cycle controls have shown premature secretory changes in the postovulatory and early luteal phase of IVF cycles. These findings suggest a profound modification of luteal endometrial development in stimulated cycles. Studies exploring the endometrium within the cycle of embryo transfer have shown a deleterious effect of severe periovulatory maturation advancement exceeding 3 days, as no clinical pregnancies were observed in this condition.

The synthesis of a set of substituted 3-aryl-7-hydroxycoumarins was performed. The study of the relations between their structure and their relative binding affinity (RBA) to human alpha and B estrogen receptors was achieved.

Pulmonary lymphangioleiomyomatosis is characterized by a proliferation of abnormal smooth muscle cells in peribronchial, perivascular and perilymphatic areas leading to cystic destruction of the pulmonary parenchyma. Recent clinical series of LAM have been helpful in better describing the various clinical and radiological forms of the disease, although our understanding of the pathophysiological mechanisms of LAM remains very limited. Significant progress has been noted in recent years with the discovery of probable antigenic and genetic similarities between pulmonary lymphangioleiomyomatosis, Bourneville tuberous sclerosis and renal angiomyolipoma. The proliferating cells in LAM share with normal smooth muscle cells their reactivity with desmine, vimentin and actin but certain are different by their reactivity with the monoclonal antibody HMB45, a common antigen marker of melanocyte differentiation cells, clear-cell lung carcinomas or renal angiomyolipomas. A loss heterozygosity in the region of the TSC2 gene in renal angiomyolipomas has been demonstrated in association with pulmonary lymphangioleiomyomatosis. The TSC2 gene is particularly implicated in the pathogenesis of Bourneville tuberous sclerosis.

The study of the relative binding affinity to steroïd hormonal receptors and of the antiproliferative action on MCF-7 cells of 3-arylcoumarines, 3-aryl-4-hydroxycoumarines, isoflavanones, isoflavan-4-ols and isoflavones, indicates a weak activity in the case of some representatives of coumarines.

The antiestrogen tamoxifen (TAM) has been successfully used to treat breast cancer expressing estrogen and progesterone receptors (ER+ and PR+). However, the development of antiestrogen resistance is frequently observed in patients following long-term treatment. To better understand the mechanism of action of TAM and its main metabolites: N-desmethyltamoxifen (N-des-TAM) and 4-hydroxytamoxifen (4-OH-TAM), their growth inhibitory effect was studied in 5 breast cancer cell lines characterized by different estrogen receptor levels: MDA-MB 231 (ER-), MCF-7 R (ER-), T47D (ER+), ZR-75/1 (ER+) and MCF-7 (ER+) trying to reproduce a cellular heterogeneity encountered in human breast tumors. In this study, the effects of TAM, N-des-TAM and 40-H-TAM on the cell growth were tested at concentrations ranging from 10(-8) to 10(-6)M with or without estradiol (10(-8)M). Only 4-OH-TAM showed a clear antiestrogen dose-dependent effect. Moreover, the finding of an antiproliferative activity at the highest dose (10(-6)M) for TAM, 4-OH-TAM and N-des-TAM in the ER- and PR- cell line MDA-MB 231 supports the hypothesis that TAM could be effective on ER+ as well as ER- tumors by an ER-independent mechanism. Despite ER+ and PR+ status after 2, 4 and 6 days of treatment, the T47D cell line displayed an increased growth rate with N-des-TAM at 10(-6)M. It should be noted that such concentration is within the range of the plasma level of N-des-TAM (10(-6)M) in patients receiving TAM per os (40 mg/day). These results and the well-known cell heterogeneity of human breast tumors may significantly account for some failure of antiestrogen treatment.

Activation of oestrogen receptor has a promoting effect in early steps of mammary carcinogenesis. Loss of oestrogen receptor, or of its functionality is associated to more aggressive and hormone unresponsive breast cancers. Anti-oestrogens are antiproliferative agents inhibiting oestrogens and growth factors action by binding to the oestrogen receptor. Assay of oestrogen and progesterone receptors, in the cytosol of primary breast cancer provides information on the differentiation and prognosis of the tumour and on the efficacy of endocrine treatment. Several oestrogen receptor variants have been detected in breast cancer, but their significance remains hypothetical. They could act in a positive constitutive fashion (e.g. anomaly of the hormone binding site with conservation of the DNA binding site) or be nonfunctional (e.g. anomaly of the DNA binding domain and or transactivation). They are often associated in the tumor with normal wild type receptors and could decrease their activity by forming nonfunctional heterodimers.

Tamoxifen is the most often prescribed non steroidal antioestrogenic agent in the world for breast cancer. Worldwide collaboration. has centralized the results, of different trials throughout the world on oral adjuvant therapy in the early stages of breast cancer. A significative regression of the tumour was observed in most cases. Moreover, recent epidemiological studies suggest that tamoxifen could prevent new contralateral primary tumours. The risk of the disease should thus be reduced by the prophylactic use of antioestrogens such as tamoxifen. Investigations using a variety of models have evaluated the effect of tamoxifen on tumour promotion and cell growth. Tamoxifen-induced growth inhibition is associated with major changes in biochemical events in cultured human breast cancer cells including cell proliferation or growth factor production. Growth inhibition of oestrogen-responsive human breast cancer cells is associated with an induced secretion of autoinhibitory polypeptides (TGF beta) and an antagonistic effect on the synthesis of proliferative proteins (TGF alpha,...). The first step in the mechanism of action of the drug is binding of tamoxifen to the oestrogen receptors. Development of resistance to tamoxifen treatment is a great problem in treatment of breast cancer patients and the mechanism of resistance will require further study: under the influence of the drug, tumours could become remodelled as selected subpopulations emerge resistant-tamoxifen. The fact that some breast cancers which are oestrogen receptor-negative respond to antioestrogen suggests that parallel but separate pathways for oestrogen and antioestrogen action may exist. This paper summarizes the results of the most recent studies concerning this promising drug.

One hundred and seven breast cancers were studied by immunohistochemistry with a monoclonal antibody revealing a protein bound to cytosolic estrogen receptors ERD5 on paraffin embedded tissue. Seventy seven per cent of the cancers were positive with a variable intensity. In half of the cases, the estrogen cytosolic receptors were also determined by biochemistry. The results were similar in 74% of cases. Estrogen receptors were detected by immunohistochemistry in 18.5% of the cancers which were negative on biochemistry. As is well known, the presence of estrogen in 18.5% of the cancers which were negative on biochemistry. As is well known, the presence of estrogen receptors is an important prognostic factor in breast cancer. Our results, together with the simplicity of the immunohistochemical method, should encourage pathologists to include this analysis in the study of surgical specimens of breast cancers.

We present our experience with the use of estradiol - bovine serum albumin (BSA) - fluorescein isothiocyanate (FITC) employed by LEE to localize estradiol receptors on frozen sections of breast carcinomas. 41 cases were studied on parallel sections with both conventional staining and a histochemical procedure. Heterogeneity of the cell population was usually found; however the histochemical result was influenced by morphological parameters. As far as histopathological types were concerned, invasive lobular carcinomas (3 cases) manifested a bright cytoplasmic fluorescence, while medullary carcinomas (3 cases) were poorly or non stained. Among infiltrating ductal carcinomas, well differentiated cases were composed of strongly fluorescent tubules, while poorly differentiated ones classified in BLOOM'S grade III were poorly stained. In most of the cases, the amount of stroma, mucus and carcinomatous or hyperplastic ductal components has to be taken in account to evaluate the fluorescence pattern of each microscopic field.

Steroidal (progestins) and non steroidal antiestrogens (tamoxifen and derivatives) are strong antiproliferative molecules when added to normal human breast cells in culture. The antiproliferative action of tamoxifen and 4-hydroxytamoxifen isomers is comparable to that observed in cultured breast cell lines. The progestin promegestone (R 5020) is a strong antiproliferative agent in the presence as well as in the absence of estradiol. Identically, at higher concentration the antiprogestin RU 486 slows down cell proliferation probably due to its progesterone agonist activity. Both progestins and antiprogestins stimulate 17 beta-hydroxysteroid dehydrogenase activity, a marker of progesterone receptor but only in estradiol primed cells.

Synthetic progestins differ in their progestomimetic and other endocrine effects. Their affinities for different steroid hormone receptors have been measured and their pharmacological activities (progestomimetic, uterotrophic, anti-estrogenic, androgen and anti-gonadotrophic) have been evaluated concomitantly. Derivatives of the pregnane series are basically progestomimetic only, whereas derivatives of the norandrostane series have distinctly androgenic and anti-estrogenic properties. A knowledge of these various activities facilitates the choice of an appropriate therapy.

In most target tissues of the female genital tract, an adequate cell differentiation can be obtained with the successive and synergistic action of estradiol (E2) and progesterone (P), essentially because the progesterone receptor (PR) synthesis implicates the previous action of E2 via its E2 receptor (ER). In normal breast, E2 stimulates the growth of the ductal system whereas the development of acini depends on P secretion. In other words, when E2 plus P are secreted by the ovaries in balanced proportions, the two hormones permit a complete and harmonious development of the mammary gland. The antiestrogenic activity of P is carried out through the decrease of ER resynthesis and stimulation of 17 beta-hydroxysteroid dehydrogenase enzyme activity, which transforms E2 into its less active metabolite estrone (E1) in the target cells. These biochemical events are well documented concerning the endometrium. They have also been observed in normal mammary cells in primary cultures as well as in breast fibroadenomas with high epithelial cellularity. Moreover, data from literature indicate that E2 could be both a direct and indirect factor of cell multiplication in cancerous cell lines. P as well as progestins have the opposite effect. Recent results from this laboratory indicate that E2 and P also have antagonistic effects on the cell multiplication of normal human mammary cells in primary culture. Therefore, the hypothesis that a lack of P during a long period of the female genital like could be a factor in the promotion of breast cancer must be considered.

38 patients with locally advanced breast cancer, were treated with a program of cytotoxic chemotherapy including Adriamycin, Cyclophosphamide, 5 Fluoro-uracile and Prednisone. The concentration of hormonal receptors (Estrogen ER and Progesterone receptor PR) in the tumor were studied before starting the chemotherapy and after one to 9 courses of chemotherapy. This therapeutic response rate was not related to the initial level of ER and PR. After chemotherapy, we observed an increase of ER level in 14 cases out of 29 (59%), of PR level in 17 out of 32 cases (53%); A therapeutic response is observed in 11 cases out of 17 when the PR concentration is increased and in 3 cases out of 15 when the PR concentration was either stable or decreased. These observations let us to suppose a selective initial activity of chemotherapy on lesser differentiated tumor cells.

The method described associates on cytological preparations, immunocytochemical reaction, counter-staining, random and morphometrical study by image analysis. It permits the quantification of estrophilin in breast carcinoma and the estimation of the heterogeneity of the tumour staining.

We report here the first case, to our knowledge, of mammary carcinoma with giant-cell stromal reaction occurring in a man. Review of literature allows to consider this carcinoma as a distinctive morphological entity. Ultrastructural cytochemical and immunohistochemical studies show that giant cells also present in metastases are non tumorous cells coming from mononuclear phagocytes cells system. This entity is peculiar by presence of inusually high titers of receptors to progesterone. Clinical evolution is still not well known.

When Rat uterus was incubated at 37 degrees with estradiol-7 alpha-butyric acid (OII-7 alpha-bu), no interference was observed with the intracellular estradiol receptors. In addition, OII-7 alpha-bu did not display estrogenic effect such as in vivo inhibition of LH secretion in Rat and in vitro increased activity of the enzyme ornithine-decarboxylase in the chick oviduct. Contrary to these negative findings, we have observed preoptic and septal cells in the guinea pig where micro-iontophoresis of OII-7 alpha-bu triggers changes of the electric activity within a second. We submit therefore, that this latter response is due to an interaction between the acid estrogen and the neuron membrane.

Estradiol 17 beta concentration and cytoplasmic estradiol binding sites were determined in the magnum of immature and developing female Quail. In the immature magnum, estradiol concentration per gram of tissue was 26 times higher than in the plasma. Early sexual development was correlated with an increase in plasma and magnum concentrations of estradiol and of cytoplasmic binding sites in the magnum. However, the ratio of binding sites concentration to that of intra-tissue of estradiol, and the intracellular distribution of estradiol (cytoplasm versus nucleus) were similar in immature and developing Quail. The results indicate that the presence of estradiol and of binding sites in the target cells of the magnum are not sufficient to induce cell proliferation.

Synthetic antiestrogens such as Tamoxifen (Nolvadex) are currently used to treat postmenopausal breast cancer. Their mechanism of action is reviewed at the cellular and molecular level, through data of the literature and the current view of the author. Synthetic antiestrogens are mostly acting directly on breast cancer cells by interacting with the estrogen receptor (RE). They prevent estrogen action by competing with estrogens on the cytosol RE. The resulting complex is partially activated resulting in its nuclear localisation and a partial and dissociated stimulation of the expression of estrogen responsive genes. The explanation of the antitumoral effect of these drugs is more controversial, since the regulation of cell proliferation is not only due to estrogens but also to other hormones and factors. The antiestrogens can therefore block cancer cell growth by inhibiting estrogen action, or by a RE medicated cytotoxic effect and/or by any other mechanism involving indirect effects, or binding to other proteins than the RE.

The different morphological methods that can be used to detect and localize estrogen receptors into the cell are reviewed. Sex steroid receptors measurements are useful for clinicians and studies on breast cancer demonstrated their predictive value in the management of patients. Beside the routinely used radiochemical assay, morphological detection of receptors can be realized by two different ways: an indirect way, using markers of estrogen and its detection when linked to the receptor. One can use radioactive estrogen and autoradiography; fluorescent estrogen and U-V microscope; or anti-estrogen antibody linkage and immunocytodetection. All these methods face two complex problems: the large diffusibility of steroid hormone and their affinity for many other ligands than their specific receptor; a direct way, irrespective of the presence or absence of hormone, using a monoclonal antibody generated against receptor protein from human breast cancer. Using this antibody, estrogen receptors are strictly localized into the nuclei of cells (no cytoplasmic localization). This appears to be the best morphological method and a useful complement of radiochemical assay.

Tamoxifen-induced fluorescence was used as a marker of hormone receptors in breast tumor cytology. Patients receiving Tamoxifen were compared to patients without such a therapy. Only those receiving this treatment showed fluorescence in their malignant cells. Moreover, in this group, such a fluorescence was noticed only in those patients with hormonal receptors in their tumor cells and not in the patients without estrogen and progesterone receptors. Such a technique seems to be a good method for predicting response to hormonal therapy.

Oestradiol and progesterone receptors concentration in endometrium is regulated by oestradiol and progesterone themselves. Oestradiol induces the two types of receptors, mainly the progesterone receptor. Progesterone decreases the production of the two types of receptors and probably increases the turnover of its own receptor. Pharmacological agents, synthetic oestrogen and progestins, behave similarly. The antioestrogen tamoxifen has a partial agonistic action of the oestrogen type on progesterone receptor induction. These observations, however, concern the whole tissue. At the cellular level, the regulation of the production of the two receptor types may indeed be different from what is observed in the entire tissue. Finally recent data on the presence of specific binding sites for antioestrogens and on receptor heterogeneity justify new studies of these regulating factors.