Cancer Control and Population Science

Epigentic features of pregnancy-associated breast cancer in Hispanic women

NCI • 1U01 CA153086
Maria Elena Martinez, PhD (Co-PI, Bernard Futscher, Cancer Biology Program)

Background
It is well recognized that risk of breast cancer increases in the period immediately following pregnancy. Breast cancers that occur in the post-partum period have more aggressive histopathological features, are more likely to metastasize, and are associated with worse patient outcomes. On average, they also affect younger women and may represent a substantial proportion of early onset breast cancer, a phenomenon that disproportionately affects racial/ethnic minority populations, such as Hispanics and African American women. Martinez ME.jpg

Specific Aims
The immediate objectives of this research project are to assess the epidemiological factors, clinical features, and epigenetic profiles of breast cancers that occur in the transient high-risk post-partum period versus those diagnosed outside of this period.

Significance
Results of the proposed work may further elucidate possible mechanisms that play a role in pre-menopausal early-onset breast cancer, particularly those mechanisms that are temporally related to a recent pregnancy.

Innovation
Success in demonstrating that the cancers that arise temporally with pregnancy harbor specific and shared silencing of specific gene sets would provide important clues as to the underlying disturbances in these tumors and possibly discovery of novel drug targets as an immediate translational outcome

Approach
Studies will be conducted in a breast cancer case series of Hispanic women, a population characterized by high parity. Results of the proposed work may further elucidate possible mechanisms that play a role in pre-menopausal early-onset breast cancer, particularly those mechanisms that are temporally related to a recent pregnancy. 

 

Vitamin D and Cancer Prevention

NCI • 1R01CA134460
Elizabeth Jacobs, PhD

Background
Although there is compelling evidence for a role for vitamin D metabolites in reducing the risk for colorectal neoplasia, the best approach for attaining optimal levels 1,25(OH)2D, especially at the cellular level, is not known, and the potential functional effects of genetic variation in the VDR and in primary enzymes responsible for anabolism and catabolism of 1,25(OH)2D at the tissue level are poorly understood. Preliminary evidence indicates that SNPs in the VDR may influence circulating concentrations of 1,25(OH)2D. Further, two enzymes, 25-hydroxyvitamin D31-alpha hydroxylase (CYP27B1) and 25-hydroxyvitamin D3 24-hydroxylase (CYP24A1), are of particular importance in homeostasis of 1,25(OH)2D, as they are involved in the conversion of 25(OH)D to 1,25(OH)2D and of 1,25(OH)2D to the inactive molecule 1,24,25(OH)3D, respectively.Jacobs_Beth.jpg

Specific Aims
1. To measure circulating 25(OH)D and 1,25(OH)2D concentrations [among 3412 participants] in three clinical trials of colorectal adenoma recurrence and assess the association between these variables and the development of recurrent adenomas.
2. To genotype [3412] study participants for variation in VDR, CYP27B1 and CYP24A1 and evaluate the association between SNPs in these genes and odds for colorectal adenoma recurrence and circulating concentrations of vitamin D metabolites in a human population.
3. To elucidate the functional effects of selected polymorphisms in the CYP27B1 and CYP24A1 genes using site-directed mutagenesis in human Caco-2 cells.
4. To further investigate the association between VDR (and the VDR FokI polymorphic variant) and β-catenin, as well as the functional influence of 1,25(OH)2D and APC on this interaction.

Significance
If vitamin D status is associated with the recurrence of precursors to colorectal cancer, there is potential for relatively simple and cost-effective preventive measures that could have immediate impact on chemoprevention. We therefore propose to investigate whether circulating 25(OH)D and 1,25(OH)2D concentrations are associated with the odds of colorectal adenoma recurrence in a large study population from three clinical trials of colorectal neoplasia. Further, because it is critical to clarify the underlying biological mechanism of action for vitamin D, we additionally propose to expand on our previous experiments evaluating the role of vitamin D in modulating β-catenin signaling.
The proposed work will have the largest sample size of any study of this kind and will allow for an in-depth analysis of whether associations between circulating concentrations of vitamin D metabolites and colorectal adenoma recurrence vary by sex or colorectal sub-site.

Innovation
The proposed study offers a unique opportunity for a novel investigation of both the functional and epidemiological effects of VDR, CYP24A1 and CYP27B1 in the colorectum. [The functional studies of the CYP enzymes will help to identify SNPs that will be used for the genotyping panel in the epidemiological component of the work, since little is currently known about these SNPs as they relate to colorectal neoplasia]. Additionally, probing the FokI polymorphic variant in VDR, combined with its potential mechanistic interplay with colonic molecular signal transduction pathways, represents a unique hallmark.

By combining our expertise in cellular and epidemiological studies, we seek to enhance our understanding of the joint effects of 1,25(OH)2D signal transduction and the FokI VDR SNP at the molecular level, while confirming their relevance to human disease. By pursuing these activities in parallel, we hope to more rapidly transition to an intervention setting targeting high risk individuals (i.e., genetically susceptible) to ultimately test vitamin D analogs as anti-cancer agents in the colon

Approach
The overall plan for the epidemiological aims of the proposed work is to pool data from 3412 participants in 3 clinical trials of colorectal adenoma recurrence and prospectively investigate whether circulating 25(OH)D and 1,25(OH)2D levels are associated with colorectal adenoma recurrence, and to evaluate whether SNPs in VDR, CYP24A1 and CYP27B1 are associated with adenoma recurrence or circulating concentrations of vitamin D metabolites]. Statistical analyses will be conducted to determine whether those with lower circulating concentrations of vitamin D at baseline were more likely to recur with a colorectal adenoma as compared to those with higher levels, and whether this relationship varies by presence of advanced adenomas, by sex or by colorectal sub-site. All participants with available samples will also be genotyped for the FokI VDR SNP as well as SNPs in the CYP24A1 and CYP27B1 enzymes, and analyzed for whether the frequency of any of the SNPs is more common in those who recurred vs. those who did not. In parallel, we will investigate the functional activity of several selected SNPs in CYP24A1 and CYP27B1 using a colonic cell culture model system. Finally, we will further explore the interactions between VDR, β-catenin, and APC using several laboratory methods.

 

Grapefruit feeding trial in overweight adult children with family history of obesity related cancer: Study of ruby red grapefruit feeding and inflammatory response

USDA • 2009-34402-19831
Cynthia Thomson, PhD

Background
Obesity remains a significant health concern among American adults and is a risk factor for several cancers including colorectal and prostate. Onset of obesity is occurring at younger ages placing the adult population at significant risk for early-onset obesity-relategrapefruit.jpgd cancer. There is evidence in breast cancer that promoting weight control in young people at genetic risk for breast cancer can significantly delay disease onset and it is highly likely that such lifestyle modification, if adopted early enough, could reduce cancer risk in people with known family history of obesity-related cancer. One reason weight control may be protective against cancer is that lean people have reduced exposure to inflammatory compounds that are secreted by adipose cells. Thus, weight control should be a primary goal for adult children of cancer survivors. 

Studies supporting the efficacy of grapefruit in promoting weight control are limited. In a recent randomized multi-arm intervention trial among obese adults, ½ grapefruit consumed daily before each meal resulted in a 1.6 kg weight loss at 12 weeks; grapefruit juice had similar weight loss effects, while apple juice did not induce weight loss. Whether the weight loss was associated with reduction in inflammatory markers was not tested. Yet inflammation is associated with cancer and grapefruit compounds have been shown to modulate colon cancer risk.

An important aspect of chronic disease risk is the inflammatory response that ensues following the ingestion of a meal, particularly an energy dense meal. Recent research has shown that consuming orange juice with a high fat, high carbohydrate meal attenuates this inflammatory response. This effect has not been assessed in an overweight population who characteristically has higher levels of inflammation nor has the potential to attenuate this response with the consumption of whole citrus fruit been evaluated.Thomson_Cyndi 2011.jpg

Specific Aims
Obesity and inflammation are risk factors for several selected cancers. Our objectives are:

1. Assess the efficacy of daily consumption of grapefruit versus no citrus on weight loss and inflammatory response in an at risk population.
2. A randomized 2-arm study of grapefruit versus no citrus among overweight men and premenopausal women 18 years and older to evaluate change in weight, body fat and inflammatory markers which may be associated with elevated cancer risk.

Significance
While we do not expect daily consumption of grapefruit be a primary therapy for obesity, if daily consumption were to demonstrate favorable effects on obesity-associated inflammation and/or body weight these data could be used to promote grapefruit consumption among overweight/ obese individuals. This would provide one behavioral strategy to be used in combination with other behavioral or therapeutic approaches to reduce the severity of this disease. Assessment of the immediate, post-prandial inflammatory/oxidant stress response to an energy dense meal has potential relevance to chronic disease risk reduction in that the behavior of eating citrus fruit with meals could help to ameliorate postprandial inflammation and oxidative stress.

Innovation
Studies supporting the efficacy of grapefruit in promoting weight control are limited. Studies linking weight loss with reduction in inflammatory markers have not been done. Yet inflammation is associated with cancer and grapefruit compounds have been shown to modulate colon cancer risk.

Approach
80 participants will be randomized to either of two groups, n=55 in the Ruby Red grapefruit group and n=55 in the control group. GROUP 1: ½ grapefruit before meals TID, limit fruits and vegetables to low bioactives, and elimination of all other citrus for 6 weeks. GROUP 2: limit fruits and vegetables to low bioactives and elimination of citrus fruits for 6 weeks. Efficacy will be evaluated by change in body weight, body fat as well as selected inflammatory markers- PGEM and thromboxane. Subjects will continue on the assigned intervention for a period of 6 weeks and will include: body weight, waist circumference, BMI, body fat by electrical impedance, blood pressure, PGEM and thromboxanes (indirect measures of COX2 inhibition). Blood sampling will include additional aliquots for future expanded metabolic analysis (insulin, lipids, oxidative stress, etc) once additional funding is secured. Efficacy of two interventions will be tested using statistical analysis which will include descriptive statistics of demographic, biochemical/ inflammatory and clinical variables. T-test comparison of body weight pre and post each feeding will serve as the primary outcome significance. 

 

 

Identification of natural product inhibitors of breast cancer bone metastasis

NCCAM • 1R21 AT005145-01A1
Janet L. Funk, PhD

BackgroundTurmeric plant.JPG
India has one of the lowest rates of breast cancer - and one of the highest levels of turmeric consumption - in the world. While clearly not proving cause and effect, this inverse relationship is of interest given existing scientific evidence that one of the many chemicals found in turmeric, curcumin, may prevent cancer cell growth. Completely unexplored, however, is the question of whether the natural mixture of interacting turmeric compounds consumed by women in India may be working together in a complex way to prevent breast cancer and its progression. Our research team is in a unique position to examine this question, having recently finished a major seven-year NIH study where the different groups of chemicals present in complex turmeric preparations, similar in composition to turmeric dietary supplements available for sale in the United States, were isolated and tested for possible medicinal effects. 

Specific Aims
Unique observations from our previous studies have led us to hypothesize that the complex mixture of chemicals found in turmeric may be particularly effective in preventing the development of breastFunk_Janet.jpg cancer bone metastases. In particular, we thought that this protective effect would be due to turmeric’s ability to inhibit cancer cell secretion of parathyroid hormone-related protein (PTHrP), a hormone central to bone metastasis development in breast cancer. Our specific aims are to test the ability of turmeric extracts to prevent the progression of breast cancer bone metastases using an experimental model.

Significance
While women diagnosed with breast cancer frequently use botanical dietary supplements, very little information is actually available regarding the safety and efficacy of such interventions. The identification of a dietary supplement that could safety minimize the risk of developing bone metastases would be of particular benefit in breast cancer survivors as most women who ultimately develop advanced disease suffer from painful bone metastases.Ground turmeric V2.jpg

Innovation
While PTHrP is known to have a central role in the development of painful lytic bone metastases in breast cancer, no therapeutic agents directly targeting PTHrP are currently available. The identification of a natural product that could limit the spread of bone metastases by specifically targeting PTHrP would be a completely novel approach to aid in both the prevention and treatment of breast cancer bone metastases.

Approach
Using human breast cancer cells that are either estrogen receptor positive (ER+) or negative (ER-), the relative abilities of chemically distinct turmeric extracts to prevent and delay the spread of bone metastases will be tested in vivo, and the role of PTHrP inhibition in mediating protective effects will be assessed.