Etiology of breast cancer III. Opportunities for prevention

Breast cancer, or its effects, may be preventable. Childbearing at an early age will confer some protection. Until there are other methods of primary prevention the physician must concentrate on secondary prevention, including screening. In presenting risk factors as criteria for screening we have attempted to make rational the use of screening technology. We should not easily accept screening for breast cancer as of proved value. Rather we must encourage clinical trials of various screening methods. In the meantime, while we engage in a moderate amount of screening we do so under the Scottish verdict of “not proven”.     

The future of cervical cancer prevention in Europe

Cervical cancer remains a significant source of disease and death in Europe. However, we now have the means to prevent virtually every case of cervical cancer through comprehensive, population-based, organised cervical cancer prevention programmes that effectively integrate cervical screening with the new technologies and vaccines that are now available. Given the potential health benefits of these programmes in reducing disease incidence and mortality, their establishment is now an ethical imperative for all European countries.     

Opportunities to improve nutrient efficiency in pigs and poultry through breeding

Efficiency of food and nutrient (including energy) use are considered the key factors in the economic and environmental performance of livestock systems. The aim of this paper is to consider the basis of genetic variation in the components that constitute dietary nutrient efficiency; and to conclude whether there would be benefit, in any relevant terms, in including these components in breeding programmes that aim to improve nutrient efficiency within pig and poultry systems of production. The components considered are (i) external, pre-ingestion losses, such as food spillage and its relation to feeding behaviour traits, (ii) digestive efficiency, (iii) maintenance requirements, (iv) net efficiency of energy and nutrient utilisation and (v) partitioning of scarce resources within productive and between productive and fitness functions. It is concluded that opportunities to exploit genetic variation exist mainly in the potential to improve the digestive efficiency of pigs and to reduce the maintenance requirements for resources mainly in hens, but also potentially in pigs. Current evidence suggests that there are very weak genetic and phenotypic correlations between components of feeding behaviour and productive traits, and little genetic variation in the net efficiency of nutrient utilisation among poultry and pig genotypes. The implication of the latter is that there would be little exploitable genetic variation in the partitioning of scarce nutrients between productive functions. Currently, there is a lack of understanding of the genetic basis of the partitioning of scarce nutrients between productive and fitness functions, and how this may impact upon the efficiency of nutrient use in pig and poultry systems. This is an area of research to which further effort might usefully be devoted.     

Molecular insight in cancer treatment and prevention

This article explores the impact of new insights in the biology of cancer on the treatment and the prevention of this disease. There are two types of targeted cancer treatment, afforded by the molecular profile of cancer. One concerns the use of agents targeted on a specific component of the cancer cells (e.g., CD20 in lymphoma) or on a specific survival function of the cancer cell (growth-factor-receptor interaction; transduction cascade). The other concerns the recognition of tumors that are more or less likely to benefit from cytotoxic chemotherapy according to their genomic or proteomic profile. Cancer prevention may benefit from new molecular insight in cancer biology as these processes allow early diagnosis of cancer, identification of patients at risk for cancer, and may provide intermediate markers for chemoprevention studies.     

Inhibition of glutaminolysis in combination with other therapies to improve cancer treatment

Targeting glutamine catabolism has been attracting more research attention on the development of successful cancer therapy. Catalytic enzymes such as glutaminase (GLS) in glutaminolysis, a series of biochemical reactions by which glutamine is converted to glutamate and then alpha-ketoglutarate, an intermediate of the tricarboxylic acid (TCA) cycle, can be targeted by small molecule inhibitors, some of which are undergoing early phase clinical trials and exhibiting promising safety profiles. However, resistance to glutaminolysis targeting treatments has been observed, necessitating the development of treatments to combat this resistance. One option is to use synergy drug combinations, which improve tumor chemotherapy’s effectiveness and diminish drug resistance and side effects. This review will focus on studies involving the glutaminolysis pathway and diverse combination therapies with therapeutic implications.     

Opportunities to improve fiber degradation in the rumen: microbiology, ecology, and genomics

The degradation of plant cell walls by ruminants is of major economic importance in the developed as well as developing world. Rumen fermentation is unique in that efficient plant cell wall degradation relies on the cooperation between microorganisms that produce fibrolytic enzymes and the host animal that provides an anaerobic fermentation chamber. Increasing the efficiency with which the rumen microbiota degrades fiber has been the subject of extensive research for at least the last 100 years. Fiber digestion in the rumen is not optimal, as is supported by the fact that fiber recovered from feces is fermentable. This view is confirmed by the knowledge that mechanical and chemical pretreatments improve fiber degradation, as well as more recent research, which has demonstrated increased fiber digestion by rumen microorganisms when plant lignin composition is modified by genetic manipulation. Rumen microbiologists have sought to improve fiber digestion by genetic and ecological manipulation of rumen fermentation. This has been difficult and a number of constraints have limited progress, including: (a) a lack of reliable transformation systems for major fibrolytic rumen bacteria, (b) a poor understanding of ecological factors that govern persistence of fibrolytic bacteria and fungi in the rumen, (c) a poor understanding of which glycolyl hydrolases need to be manipulated, and (d) a lack of knowledge of the functional genomic framework within which fiber degradation operates. In this review the major fibrolytic organisms are briefly discussed. A more extensive discussion of the enzymes involved in fiber degradation is included. We also discuss the use of plant genetic manipulation, application of free-living lignolytic fungi and the use of exogenous enzymes. Lastly, we will discuss how newer technologies such as genomic and metagenomic approaches can be used to improve our knowledge of the functional genomic framework of plant cell wall degradation in the rumen.     

Opportunities for manipulating the seed protein composition of wheat and barley in order to improve quality

Wheat and barley are the major temperate cereals, being used for food, feed and industrial raw material. However, in all cases the quality may be limited by the amount, composition and properties of the grain storage proteins. We describe how a combination of biochemical and molecular studies has led to an understanding of the molecular basis for breadmaking quality in wheat and feed quality in barley, and also provided genes encoding key proteins that determine quality. The control of expression of these genes has been studied in transgenic tobacco plants and by transient expression in cereal protoplasts, providing the basis for the production of transgenic cereals with improved quality characteristics.     

Importance of probiotics in the prevention and treatment of colorectal cancer

Colorectal cancer (CRC) remains one of the most common and deadly cancers. Intestinal gut microflora is important to maintain and contributes to several intestinal functions, including the development of the mucosal immune system, absorption of complex macromolecules, synthesis of amino acids/vitamins and the protection against pathogenic microorganisms. It is well known that the gut microbiota changes or dysbiosis may have an essential impact in the initiation and promotion of chronic inflammatory pathways and also have a profound different genetic and epigenetic alterations leading to dysplasia, clonal expansion, and malignant transformation. Probiotic bacteria has antitumor activity with various mechanisms such as nonspecific physiological and immunological mechanisms. This review evaluates the effects of microbiota and probiotics in clinical trials, in vitro and animal model studies that have explored how probiotic against cancer development and also discusses the possible immunomodulatory mechanisms. Several mechanisms alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host's immune response; antiproliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase; reduces the enteropathogenic complications before and after colon cancer surgery and improve diarrhea and it's have been able to create the integrity of gut mucosal and have stimulatory effects on the systemic immune system and prevent the CRC metastasis. Research in clinical trials encouraging findings that support a role of probiotics in CRC prevention and improve the safety and effectiveness of cancer therapy even though additional clinical research is still necessary.     

Second primary cancer following treatment for cervical cancer.

A follow-up study of 7535 women in Ontario was carried out to assess the occurrence of second primary cancers following the treatment of invasive carcinoma of the cervix between 1960 and 1975. The study was part of a larger international investigation of late radiation effects in patients with cervical cancer. Data were collected on the date and the type of treatment for cervical cancer and on the occurrence of second primary cancers diagnosed before 1980. Observed and expected numbers of second primary cancers, the latter determined according to Ontario incidence rates, were compared for individual sites and for all sites combined. There were significantly more primary cancers of the lung than expected (64 v. 15.52) but significantly fewer second primary cancers of the breast (56 v. 105.01) and colon (27 v. 43.31). Overall, there were significantly fewer (p less than 0.05) observed second primary cancers than expected (280 v. 394). Although the median follow-up period was less than 10 years there was no marked evidence of an excess of radiation-induced second primary cancers.     

Plant-derived epigenetic modulators for cancer treatment and prevention

Carcinogenesis is a complex and multistep process that involves the accumulation of successive transformational events driven by genetic mutations and epigenetic alterations that affect major cellular processes and pathways such as proliferation, differentiation, invasion and survival. Massive deregulation of all components of the epigenetic machinery is a hallmark of cancer. These alterations affect normal gene regulation and impede normal cellular processes including cell cycle, DNA repair, cell growth, differentiation and apoptosis. Since epigenetic alterations appear early in cancer development and represent potentially initiating events during carcinogenesis, they are considered as promising targets for anti-cancer interventions by chemopreventive and chemotherapeutic strategies using epigenetically active agents. In this field, plant-derived compounds have shown promise. Here, we will give an overview of plant-derived compounds displaying anticancer properties that interfere with the epigenetic machinery.     

Efficacy of vaccination against HPV infections to prevent cervical cancer in France: present assessment and pathways to improve vaccination policies

Background

Seventy percent of sexually active individuals will be infected with Human Papillomavirus (HPV) during their lifetime. These infections are incriminated for almost all cervical cancers. In France, 3,068 new cases of cervical cancer and 1,067 deaths from cervical cancer occurred in 2005. Two vaccines against HPV infections are currently available and vaccination policies aim to decrease the incidence of HPV infections and of cervical cancers. In France, vaccine coverage has been reported to be low.

Methods

We developed a dynamic model for the heterosexual transmission of Human Papillomavirus types 16 and 18, which are covered by available vaccines. A deterministic model was used with stratification on gender, age and sexual behavior. Immunity obtained from vaccination was taken into account. The model was calibrated using French data of cervical cancer incidence.

Results

In view of current vaccine coverage and screening, we expected a 32% and 83% reduction in the incidence of cervical cancers due to HPV 16/18, after 20 years and 50 years of vaccine introduction respectively. Vaccine coverage and screening rates were assumed to be constant. However, increasing vaccine coverage in women or vaccinating girls before 14 showed a better impact on cervical cancer incidence. On the other hand, performing vaccination in men improves the effect on cervical cancer incidence only moderately, compared to strategies in females only.

Conclusion

While current vaccination policies may significantly decrease cervical cancer incidence, other supplementary strategies in females could be considered in order to improve vaccination efficacy.     

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

This article describes the origins and evolution of "antiestrogenic" medicines for the treatment and prevention of breast cancer. Developing drugs that target the estrogen receptor (ER) either directly (tamoxifen) or indirectly (aromatase inhibitors) has improved the prognosis of breast cancer and significantly advanced healthcare. The development of the principles for treatment and the success of the concept, in practice, has become a model for molecular medicine and presaged the current testing of numerous targeted therapies for all forms of cancer. The translational research with tamoxifen to target the ER with the appropriate duration (5 years) of adjuvant therapy has contributed to the falling national death rates from breast cancer. Additionally, exploration of the endocrine pharmacology of tamoxifen and related nonsteroidal antiestrogen (e.g. keoxifene now known as raloxifene) resulted in the laboratory recognition of selective ER modulation and the translation of the concept to use raloxifene for the prevention of osteoporosis and breast cancer. However, the extensive evaluation of tamoxifen treatment revealed small but significant side effects such as endometrial cancer, blood clots and the development of acquired resistance. The solution was to develop drugs that targeted the aromatase enzyme specifically to prevent the conversion of androstenedione to estrone and subsequently estradiol. The successful translational research with the suicide inhibitor 4-hydroxyandrostenedione (known as formestane) pioneered the development of a range of oral aromatase inhibitors that are either suicide inhibitors (exemestane) or competitive inhibitors (letrozole and anastrozole) of the aromatase enzyme. Treatment with aromatase inhibitors is proving effective and is associated with reduction in the incidence of endometrial cancer and blood clots when compared with tamoxifen and there is also limited cross resistance so treatment can be sequential. Current clinical trials are addressing the value of aromatase inhibitors as chemopreventive agents for postmenopausal women.