Raloxifene is a nonsteroidal selective estrogen receptor modulator that has favorable effects on markers of cardiovascular risk and has been associated with a reduced risk of coronary heart disease (CHD) in postmenopausal women. Raloxifene also has antiestrogenic effects on the breast and in animals has suppressed the growth of estrogen-stimulated mammary cancers. The Raloxifene Use for The Heart (RUTH) trial was a randomized, double-blind, placebo-controlled study carried out at 177 sites in 26 countries. The 10,101 participants were women aged 55 and older who were at least 12 months postmenopausal and who either had established CHD or were at increased risk. They were assigned to receive either 60 mg raloxifene orally each day or a placebo. The 2 groups were similar in baseline characteristics except for slightly higher cardiovascular risk scores for women assigned to raloxifene. During a median follow up of 5.6 years, no significant differences were found with respect to deaths from coronary causes, nonfatal myocardial infarction, or hospital admission because of an acute coronary syndrome. Women with established CHD and those at increased risk for CHD had similar outcomes. For the primary coronary outcome, the results of as-treated analyses were comparable to those of intention-to-treat analyses. Raloxifene was associated with a decreased incidence of invasive breast cancer; the hazard ratio was 0.56 with a 95% confidence interval of 0.38 to 0.83. The absolute risk reduction for every 1000 women given raloxifene for 1 year was 1.2 cases for both invasive breast cancer and estrogen receptor-positive invasive breast cancer. Among secondary outcomes, the incidence of stroke did not differ significantly between the raloxifene and placebo groups, but fatal strokes were 49% more frequent in raloxifene-treated women. Venous thromboembolic events were 44% more frequent in the raloxifene group. Incidence rates of all breast cancers and of clinical vertebral fractures were lower in the raloxifene group. More than 90% of women in both groups reported adverse events. Rates of discontinuance because of side effects were 22% in the raloxifene group and 20% in the placebo group. Serum levels of low-density lipoprotein cholesterol declined in women given raloxifene but increased in placebo recipients. Levels of high-density lipoprotein cholesterol increased in both groups but more so in women treated with raloxifene. Raloxifene treatment, given for a median of over 5 years to postmenopausal women at increased risk of CHD, did not significantly alter CHD risk in the RUTH study. Its beneficial effects in lowering the risk of invasive breast cancer and vertebral fracture must be weighed against increased risks of fatal stroke and venous thromboembolism.

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Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women

Amplification of the TNK2 gene in primary tumours correlates with poor prognosis. In accordance, TNK2 overexpression was shown to promote invasion of cancer cells – but the mechanism by which TNK2 mediates these effects is unresolved. TNK2 was suggested to regulate Cdc42-driven migration by activation of breast cancer antioestrogen resistance 1 (BCAR1); however, distinct from this effect is evidence for a role of TNK2 in the regulation of epidermal growth factor receptor (EGFR) endocytosis and degradation. In the present study we sought to investigate whether negative targeting of TNK2 by siRNA could be used to inhibit cancer cell invasion, to establish the contribution of its effect on the EGFR and to consequently attempt to resolve the issue of TNK2's mechanism of action. We used siRNA to knockdown expression of TNK2 and its proposed effector BCAR1 in order to analyse the effect of this knockdown on cancer cell behaviour in vitro. We examined morphological changes using phase-contrast microscopy and immunohistochemistry. Functional parameters examined included apoptosis, proliferation, migration and invasion. We also performed flow cytometry analysis to examine EGFR cell surface expression and carried out western blot to examine the total EGFR levels. We observed that targeting of TNK2 by siRNA in breast cancer cells resulted in distinct morphological changes characterised by a stellate appearance and an absence of protrusions at membrane edges. These changes were not recapitulated upon siRNA targeting of BCAR1. We thus hypothesised that a component of the effects induced by TNK2 may be independent of BCAR1. Consistent with the idea of an alternative mechanism for TNK2, we observed that TNK2 associates with activated EGFR in breast cancer cells in a TNK2-kinase-independent manner. Furthermore, we demonstrated that TNK2 functions to maintain EGFRs on the cell surface. We could demonstrate that the main functional effect of activating these surface EGFRs in breast cancer cells is stimulation of migration. In accordance, TNK2 silencing by siRNA led to a significant reduction in cell surface EGFR and to a concomitant decrease in the migratory and invasive capacity of breast cancer cells. Our data suggest that TNK2 can enhance migration and invasion of breast cancer cells via preservation of EGFR expression, notwithstanding its previously reported signalling via BCAR1, explaining its oncogenic behaviour in vitro and correlation with metastatic human breast cancer in vivo.

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TNK2 preserves epidermal growth factor receptor expression on the cell surface and enhances migration and invasion of human breast cancer cells

The forgotten woman's cancer: vulvar squamous cell carcinoma (VSCC) and a targeted approach to therapy

Breast cancer is a complex, molecular disease, in which a number of cellular pathways involving cell growth and proliferation, such as the MAPK, RB/E2F, P13K/AKT/mTOR, and TP53 pathways, are altered. These pathways represent molecular mechanisms that are composed and regulated by various genes. The genes that are altered in terms of cell growth and proliferation include the oncogenes HER2, c-MYC, and RAS, the ER genes, and the genes for cell cyclin D1 and E, and the tumor suppressor genes RB, TP53, and PTEN, and the breast cancer susceptibility genes BRCA1 and BRCA2. Although the nature of breast cancer is complex and has frustrated previous attempts at treatment or prevention, the elucidation of its molecular nature over the last several decades is now providing targets for effective therapies to treat the disease and hopefully one day to prevent it.

The molecular genetics of breast cancer and targeted therapy

Drug resistance is one of the major obstacles limiting the success of cancer chemotherapy. Biological mechanisms contributing to drug resistance may be present de novo and related to inherent features or may be raised after exposure to anticancer drugs. In recent years, both clinical observations and experimental studies suggested that steroid hormones and their receptors might also affect the therapeutic efficacy of antineoplastic drugs. Estrogens and estrogen receptors (ER) are well-known for their critical roles in the development and progression of breast tumors. It has long been known that breast tumors expressing ERα protein (ERα+) behave in a fundamentally different fashion than ERα-negative (ERα-) tumors with regard to their responses to hormonal therapy. Data obtained from both laboratory and clinical investigations suggested that some chemotherapeutic agents are clearly less effective in ERα+ tumors than ERα- tumors, although the mechanisms of ERα-mediated chemoresistance are not entirely clear. Moreover, recent studies from our laboratory and others demonstrated that the combination of antiestrogenic agents with chemotherapeutic drugs is of significant therapeutic benefit in ERα+ breast cancer over chemotherapy alone. In addition, the ERα-derived peptides, microRNAs specifically targeting ERα, as well as agents targeting estrogen-related receptors (ERRs) may hold promise to sensitize ERα+ breast tumors to chemotherapy. Considering that ERs are expressed in ˜ 65% of human breast cancer, the ERα-mediated chemoresistance has become a big challenge for clinical treatment. The hope to overcome this drug resistance relies on further clarification of specific pathways or molecules contributing to the resistance. More exhaustive and systematic studies are essential to reach deeper understandings on the underlying mechanisms and to develop novel approaches to sensitize ERα+ breast tumors to chemotherapy.

The role of estrogen and estrogen receptors in chemoresistance.

Purpose of review This review summarizes the continuing value of some therapeutic drugs and new agents under development for the treatment of breast cancer. Recent findings Overexpression and activation of various growth factor receptors occurs frequently in human breast cancer. Therapeutic approaches mainly involve the epidermal growth factor receptor family, insulin-like growth factor receptor and vascular endothelial growth factor receptor. Therapeutic agents targeting these receptors include the monoclonal antibodies trastuzumab and pertuzumab, and the small-molecule inhibitors gefitinib and erlotinib. Other small-molecule and dual inhibitors are in development, some of which have been demonstrated to have higher efficacy in the treatment of breast cancer. The selective estrogen receptor modulators and aromatase inhibitors continue to be valuable in the endocrine therapy of breast cancer. These drugs have been shown to have higher efficacy than conventional therapy agents, and to have extensive potential, especially in the treatment of postmenopausal women with advanced breast cancer. Summary Approved agents including epidermal growth factor receptor-targeted inhibitor, selective estrogen receptor modulators and aromatase inhibitors continue to be valuable in treating breast cancer. To overcome the acquired resistance caused by these agents and to enhance the therapy effect, the development of new and specific dual inhibitors targeting various growth factor receptors will be important in the future.

Fang Liu

Papers

New agents in development for breast cancer.