Current Understanding of Mitochondrial DNA in Breast Cancer

Abstract:  The recent surge in mitochondrial research has been driven by the identification of mitochondria-associated diseases and the role of mitochondria in apoptosis and aging. Mitochondrial DNA (mtDNA) has been proposed to be involved in carcinogenesis because of its high susceptibility to mutations and limited repair mechanisms in comparison to nuclear DNA. As mtDNA lacks introns, it has been suggested that most mutations will occur in coding sequences. The subsequent accumulation of mutations may lead to tumor formation. By virtue of their clonal nature, high copy number and high frequent mutations may provide a powerful molecular biomarker for the detection of cancer. It has been suggested that the extent of mtDNA mutations might be useful in the prognosis of cancer outcome and/or the response to certain therapies. In this review article, we aim to provide a brief summary of our current understanding of mitochondrial genetics and biology, review the mtDNA alterations reported in breast cancer, and offer some perspectives as to the emergence of mtDNA mutations, including their functional consequences in cancer development, diagnostic criteria, and therapeutic implications.     

DNA Fingerprints Provide a Patient-Specific Breast Cancer Marker

Background Detection of systemic breast cancer recurrence is limited by lack of universally expressed tumor cell markers. We hypothesized that a test that detects genetic alterations specific to breast cancer cells of an individual patient would provide a superior cancer marker.Methods DNA was extracted from blood, primary tumor, and axillary lymph nodes of 33 breast cancer patients and normal breast tissue of 12 control patients. A patients genome was scanned by PCR amplification between Alu sequences. A DNA fingerprint of approximately 17–40 bands was produced for comparison between normal blood and sampled tissues.Results There were 7 stage I, 18 stage II, 7 stage III, and 1 stage IV breast cancer cases; 33 of 33 cancer cases showed DNA fingerprint differences between blood and primary tumor (P < .0001).This test predicted 100% of positive nodes. No false-negatives occurred, and in two cases malignancy was detected in histologically negative nodes. Three of the 12 controls showed a single similar band change.Conclusions DNA fingerprinting is a method for detecting and characterizing genetic alterations specific to an individual patients primary tumor in 100% of cases tested. These specific changes were also identified in 100% of positive nodes, proving the capacity of the test to detect metastases.     

Breast Cancer and Transplantation

Breast cancer is an important cancer among solid organ transplant recipients. While the incidence of breast cancer in solid organ transplant recipients is comparable to the age‐matched general population, the outcomes are generally poor. Interventions such as cancer screening that preclude the development of late‐stage disease through early detection are not well studied, and clinical practice guidelines for cancer screening rely solely on recommendations from the general population. Among patients with a prior breast cancer history, disease recurrence after transplantation is a rare but fearful event. Once disease recurs, the risk of death is high. The focus of this review is to present the epidemiology of breast cancer in solid organ transplant recipients, screening and preventive strategies for those who may be at risk, novel genomic profiling for determining tumor progression, and the newer targeted interventions for recipients who have developed breast cancers after solid organ transplantation.     

Affluence and Breast Cancer

High income, high socioeconomic status, and affluence increase breast cancer incidence. Socioeconomic status in USA breast cancer studies has been assessed by block‐group socioeconomic measures. A block group is a portion of a census tract with boundaries that segregate, as far as possible, socioeconomic groups. In this study, we used US Census income data instead of block groups to gauge socioeconomic status of breast cancer patients in relationship with incidence, prognostic markers, and survival. US state breast cancer incidence and mortality data are from the U.S. Cancer Statistics Working Group, United States Cancer Statistics: 1999–2011. Three‐Year‐Average Median Household Income by State, 2010 to 2012, is from the U.S. Census Bureau, Current Population Survey, 2011 to 2013 Annual Social and Economic Supplements. County incomes are from the 2005–2009 American Community Survey of the U.S. Census Bureau. The American Community Survey is an ongoing statistical survey that samples a small percentage of the population yearly. Its purpose is to provide communities the information they need to plan investments and services. Breast cancer county incidence and survival data are from the National Cancer Institute's Surveillance, Epidemiology and End Results Program (SEER) data base. We analyzed SEER data from 198 counties in California, Connecticut, Georgia, Hawaii, Iowa, New Mexico, Utah, and Washington. SEER uses the Collaborative Stage (CS) Data Collection System. We have retained the SEER CS variables. There was a significant relationship of income with breast cancer incidence in 50 USA states and the District of Columbia in White women (r = 0.623, p < 0.001). There was a significant relationship between node involvement and income in Whites in 198 USA counties. Income was significantly correlated with 5‐year relative survival in Whites with localized breast cancer. Income was not correlated with 5‐year survival of Black race (p = 0.364) or other races (p = 0.624). The multivariate general linear model with income as covariate, 5‐year survival by race as a dependent variable, showed a significant effect of income and White race on 5‐year survival (p < 0.001), unrelated to Black race (p = 0.780) or other races (p = 0.618). In men, we found a nonsignificant positive correlation between county breast cancer incidence and income (r = 0.098, p = 0.168). Breast cancer risk factors, such as delayed childbirth, less breast‐feeding, and use of hormone supplements, are more common in affluent women. Affluent women are more likely to have mammograms, which detect many cancers that might not otherwise be diagnosed. In addition, women in certain affluent ethnic groups—Ashkenazi Jews, Icelanders and the Dutch—are more likely to carry genetic mutations known to predispose to breast cancer. We hypothesize that women with more income can afford better cancer care and survive longer than poorer women. But our hypothesis does not explain why this effect should be limited to White women; or why node involvement increased with income in White women but not in Blacks or Hispanics. Further studies may be worthwhile.     

Smoking and Breast Cancer

The potential role of smoking in breast cancer risk has been the subject of over 100 publications, numerous scientific reviews, and animated debate. Tobacco exposure is a well-established cause of lung cancer, and is thought to account for nearly one third of all cancer deaths. Tobacco smoke contains thousands of chemicals, many of which are known to be mammary carcinogens. Although not initially thought to be a tobacco-related cancer, over the last several decades evidence has been accumulating on the role of both active smoking and secondhand smoking in the etiology of breast cancer. The human health evidence has been systematically evaluated not only by several independent researchers but also by several expert agency panels including those of the U.S. Surgeon General, the International Agency for Research on Cancer, the California Environmental Protection Agency, and a coalition of Canadian health agencies. Although the assessments have varied with time and across reviewers, the most recent weight of the evidence has suggested a potentially casual role for active smoking and breast cancer, particularly for long-term heavy smoking and smoking initiation at an early age. The role of secondhand smoking and breast cancer is less clear, although there has been some suggestion for an increased risk for premenopausal breast cancer. Recent studies evaluating the possible modifying role of polymorphisms in genes involved in the metabolism of tobacco products, particularly NAT2, have contributed another dimension to these assessments, although to date that evidence remains equivocal.     

蛋白组学与乳腺癌

随着人类基因组计划的初步完成 ,蛋白组学成为新的研究热点。依托于双向凝胶电泳技术的进步和以基质辅助的激光解吸飞行时间质谱为代表的质谱技术的提高 ,以及生物信息学的引入 ,蛋白组学研究进展迅速。乳腺癌作为常见的恶性肿瘤之一 ,其在蛋白组学方面的研究亦有广泛而深入的开展 ,这项技术不仅有助于进一步加深理解乳腺癌发生、发展的分子基础 ,而且具有提高乳腺癌诊治水平的潜力     

Metals and Breast Cancer

Metalloestrogens are metals that activate the estrogen receptor in the absence of estradiol. The metalloestrogens fall into two subclasses: metal/metalloid anions and bivalent cationic metals. The metal/metalloid anions include compounds such as arsenite, nitrite, selenite, and vanadate while the bivalent cations include metals such as cadmium, calcium, cobalt, copper, nickel, chromium, lead, mercury, and tin. The best studied metalloestrogen is cadmium. It is a heavy metal and a prevalent environmental contaminant with no known physiological function. This review addresses our current understanding of the mechanism by which cadmium and the bivalent cationic metals activate estrogen receptor-α. The review also summarizes the in vitro and in vivo evidence that cadmium functions as an estrogen and the potential role of cadmium in breast cancer.     

Breast Cancer Genes

Abstract: The identification of familial breast cancer genes heralds an era of directed breast cancer treatment. Currently, two hereditary breast cancer genes have been identified, BRCA-1 and BRCA-2 . Although accounting for only approximately 5% of all breast cancers, they are being used to identify women with germ-line alterations that are at high risk of developing breast or ovarian cancer. With the identification of such genes comes a need for consideration of the ethical issues associated with testing. These genes are also being examined from a biochemical standpoint encompassing both their biological roles and biochemical pathways in which they reside. Such studies are likely to lead to novel breast cancer therapies.     

Breast Cancer Prevention

Breast cancer is the most common cancer in women with 232,670 new cases estimated in the USA for 2014. Approaches for reducing breast cancer risk include lifestyle modification, chemoprevention, and prophylactic surgery. Lifestyle modification has a variety of health benefits with few associated risks and is appropriate for all women regardless of breast cancer risk. Chemoprevention options have expanded rapidly, but most are directed at estrogen receptor positive breast cancer and uptake is low. Prophylactic surgery introduces significant additional risks of its own and is generally reserved for the highest risk women.     

Lactation and Breast Cancer Risk

Breast cancer is a common disease with few practical preventive measures. The recent evidence that lactation, like other reproductive experiences, is associated with a modest reduction in breast cancer risk is therefore of great interest. Overall, the reduction in risk appears to be about 20% for ever breast feeding and is even greater for women with histories of prolonged lactation, or who initiate breast feeding at young ages. In many studies this risk reduction seems to be limited to premenopausal women. It appears unlikely that this inverse association is attributable either to higher risk among women who use lactation suppressants or who have difficulty either starting or continuing breast feeding. While a strong or consistent protective effect of lactation on breast cancer risk has not been observed in some large and well conducted studies, this likely reflects the limited breast feeding practices among modern women. If early, exclusive and extended breast feeding is necessary to achieve a breast cancer risk reduction, future studies among U.S. women may be unable to clarify this association.