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There is an increasing body of evidence demonstrating that growth factor networks are highly interactive with oestrogen receptor (ER) signalling in the control of breast cancer growth. As such, tumour responses to anti- hormones are likely to be a composite of the ER and growth factor inhibitory activity of these agents. The current article examines the modulation of growth factor networks during endocrine response, and presents in vitro and clinical evidence that epidermal growth factor receptor signalling, maintained in either an ER-dependent or -independent manner, is critical to anti- hormonal-resistant breast cancer cell growth. The considerable potential of the epidermal growth factor receptor-selective tyrosine kinase inhibitor, ZD 1839 (Iressa; AstraZeneca) to efficiently treat, and perhaps even prevent, endocrine-resistant breast cancer is highlighted.
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ABSTRACT
Loss of oestrogen-receptor (ER) expression and function may explain the development of tamoxifen resistance in breast cancer. In 72 paired biopsies the immunohistochemical expression of ERs was reduced from 51% before tamoxifen treatment to 29% at progression or relapse, with a reduction in mean H-score from 90 to 61 (P<0.001, paired t-test). However, there was no significant change in progesterone receptor (PgR) or pS2 expression, markers of ER function. Tumours which developed acquired resistance after primary tamoxifen treatment frequently remained ER+ve at relapse (61%) and continued to express PgR or pS2. In contrast, those which progressed with de novo resistance were all ER−ve, although 6 of these tumours expressed high levels of PgR and/or pS2. In tumours which recurred during adjuvant tamoxifen therapy, the frequency and quantitative level both of ERs and of PgR were significantly reduced. These data imply that separate mechanisms of tamoxifen resistance may exist in these clinical subgroups.
Endocrine-Related Cancer (1995) 2 105-110
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ABSTRACT
Gross cystic breast disease frequently occurs in premenopausal women and women with apocrine cysts may have an increased risk of developing breast cancer. Many steroids, growth factors, cytokines and proteins have now been identified in breast cyst fluid (BCF), but it is not yet known whether any of these factors may be associated with an increased risk for cancer, or if these factors have a functional role within the breast. In this study we show that concentrations of the cytokine interleukin-2 are higher in BCF with a low electrolyte ratio, whereas albumin concentrations are increased in BCF with a high Na+/K+ ratio. As albumin has been shown to potentiate the ability of growth factors, such as insulin-like growth factor-I (IGF-I), to stimulate oestradiol-17β hydroxysteroid dehydrogenase (E2DH) (reductive) activity in breast cancer cells, we have examined the ability of other proteins which are found in breast secretions (α-lactalbumin, lactoferrin) or BCF (gross cystic disease proteins-15 and -24) to potentiate the action of this growth factor. While lactoferrin had no effect on E2DH, the other proteins tested significantly potentiated the effect of IGF-I on the activity of this enzyme. Recombinant human albumin also acted synergistically with IGF-I to stimulate E2DH activity, suggesting that the ability of albumin to potentiate growth factor action is an intrinsic property of the molecule itself, rather than being due to the presence of a ligand which is bound to the molecule. Results from these investigations suggest that proteins found in breast secretions and BCF may have a functional role in regulating oestrogen synthesis in breast tissues.
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Biopharmaceutical Research Unit, Department of Biology, Novo Nordisk A/S, Novo Nordisk Park G8.1.55, Maaloev DK-2760, Denmark
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, transgenic over-expression of PRL induced formation of mammary tumours ( Wennbo et al . 1997 ), many of which were oestrogen receptor (ER)-positive ( Rose-Hellekant et al . 2003 ). PRLR knockout studies have shown a decrease of the mammary tumour growth
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The oestrogen receptor (ER) status of 2660 patients with primary breast cancer has been related to the effect of different adjuvant systemic therapies on survival. However, as patients in the various treatment groups also had different prognostic features comparison between treatments was difficult. Over 90% of patients receiving tamoxifen (Tam) were postmenopausal compared with <20% of those receiving chemotherapy (CT). The latter had more positive nodes (85% vs 54%) and grade III tumours (54% vs 30%) than the Tam group. The combined CT and Tam group had similar characteristics to the CT alone group. The current reported increase in the proportion of women with ER+ tumours is explained by immunohistochemical analysis of ER and screening programmes. ER status was unrelated to survival in patients with small, low grade, node-negative tumours which was no different from that expected for age-matched women taken from the general population. The value of adjuvant treatment in these patients is therefore questionable. In those given any adjuvant treatment, survival of women with ER+ tumours was prolonged, with the greatest effect being seen in those receiving Tam. Patients with ER- tumours benefited from CT but the addition of Tam to CT improved survival only in those with ER+ tumours. ER status is now established as a major predictive factor for treatment selection in primary disease. Studies of prognostic and predictive markers may be invalidated by use of adjuvant therapy and selection criteria for different treatments. Survival will be influenced by both tumour biology and therapy. This important consideration must be remembered when analysing new markers, particularly in small studies.
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al. 2004 ). That said, high consumption of phytoestrogens, which are very weak mimics of natural oestrogens, are associated with a lower incidence of breast cancer (Limer & Spiers 2004). Phytoestrogens, HRT, and breast cancer
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Ovarian cancer accounts for 5% of all cancer deaths in Western countries and is the most frequent cause of gynaecologic cancer mortality. The incidence varies with age between 1% and 14% with a peak rate in the eighth decade, and in the majority of cases, the disease has already spread beyond the pelvic cavity at time of diagnosis. Although in the last decades the introduction of cisplatin-based chemotherapy resulted in an improvement of patient survival, the percentage of recurrent disease is high even in those patients who achieve a complete response to chemotherapy, so that more than 80% of patients with advanced stage of disease die within 5 years (Copeland & Gershenson 1986). At present the prognostic characterisation of ovarian cancer patients, based on clinico-pathological parameters, such as stage, histology, grade and residual tumour after surgery, seems to be inadequate, since patients with similar clinico- pathological characteristics often experienced different clinical outcome. Therefore, the identification of biological factors related to tumour aggressiveness could be relevant in order to identify patients with different prognosis and chance to respond to chemotherapy, thus allowing the selection, at time of initial diagnosis, of high risk patients needing more aggressive therapy or alternative treatment, and a closer follow-up. Among the biological parameters proposed as possible prognostic factors in ovarian cancer much attention has been focused on endocrine factors and especially on steroid hormones and their receptors. Although several epidemiological and in vitro evidences have demonstrated that, similarly to breast and endometrial cancer, ovarian cancer cell biology could be influenced by the biochemical pathways promoted by the interaction of estrogens and progesterone with their specific receptors (ER, PR) conflicting data have been reported about the possible clinical role of ER and PR in this neoplasm. This review is aimed: a) to summarise the informations about the influence of steroid hormones and their receptors in the biology of ovarian cancer in in vitro models as well as in primary tumours;b) to investigate the association of steroid hormone receptor expression with the clinico-pathological parameters and the clinical outcome in ovarian cancer patients.c) to report the data of the literature about the rationale and the results of endocrine therapy in ovarian cancer.
