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Diet, Epigenetics and Breast Cancer

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1 Diet, Epigenetics and Breast Cancer
Shuk-Mei Ho Ph.D. Jacob G. Schmidlapp Professor and Chair of Department of Environmental Health Director, Center for Environmental Genetics Director, Microarray and Genomic Core Associate Director, Cincinnati Cancer Center University of Cincinnati College of Medicine

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3 Lamarckian Evolution Jean-Baptiste Lamarck (1744–1829), a French naturalist, was among the first group of scholars advancing the idea that evolution occurred and proceeded in accordance with natural laws. Wikipedia (http://en.wikipedia.org/wiki/Jean-Baptiste_Lamarck 11/16/2010)

4 Major thesis of Lamarckian Evolution:
The environment brings up new needs, resulting in adaptive changes in animals Lamarck proposed the theory of "inheritance of acquired characters.” He believed animals including the human lose unused traits and develop useful characteristics that are inherited by their offspring He cited examples such as blindness in moles, the absence of teeth in birds, Wikipedia (http://en.wikipedia.org/wiki/Jean-Baptiste_Lamarck 11/16/2010)

5 and the elongated necks of giraffes as evidence in support of his theory His ideas were well accepted by most naturalists until Charles Darwin published his “Origin of Species”

6 Darwinian Evolution- Natural Selection
Charles Robert Darwin (1809 –1882), an English naturalist, proposed and published his highly popular evolution theory known as natural selection as a book entitled “On the Origin of Species.” It explains how all species of life have evolved over time from common ancestors. Slowly but surely…..Darwin wrote, "…Natural selection acts only by taking advantage of slight successive variations; she can never take a great and sudden leap, but must advance by short and sure, though slow steps." Wikipedia (http://en.wikipedia.org/wiki/Charles_Darwin 11/16/2010)

7 Darwinian Evolution- Natural Selection
Population speciation: Evolution is a process that occurs in the heritable characteristics of a population over time. However, the Darwian evolution fails to explain the transmission of acquired characters such as a significant increase in breast cancer risk among Asian-American women within one generation after immigration. Wikipedia (http://en.wikipedia.org/wiki/Charles_Darwin 11/16/2010)

8 Genetic Basis of Disease Variability
In the past, susceptibility of disease was believed to be determined solely by inheritable information carried on the primary sequence of the DNA Aberrant changes in linear DNA sequence result in mutations, deletions, gene fusion, tandem duplications, or gene amplifications causing disregulation of gene expression that underlies the genesis of disease Tang WY and Ho SM Reviews in Endocrine & Metabolic Disorders 2007

9 Genetic charges give rise to alternative traits that are better fits for a new environment : e.g.. Skin color (I) 10,000 yr 10,000 yr 30,000 yr 35,000 yr 45,000 yr 50,000 yr

10 Genetic charges give rise to alternative traits that are better fits for a new environment : e.g.. Skin color (I) 10,000 yr 10,000 yr 30,000 yr 35,000 yr 45,000 yr 50,000 yr

11 Conrad H. Waddington (1905-1975) – a developmental biologist
The term epigenetics means outside conventional genetics Waddington exposed Drosophila pupae to heat and observed altered wing-vein patterns (1940) when the flies emerged. The altered phenotype persisted in the population long after the stimulus was removed, suggesting that exposure to an environmental factor during a critical developmental window could produce a lifetime phenotype-change He argued that this phenomenon represented an acquired character had been assimilated into the genetic code of the flies and referred to this as “genetic assimilation,” or “epigenetics” in modern terminology Nature Reviews Genetics (1977 The Royal Society) Tang WY and Ho SM Reviews in Endocrine & Metabolic Disorders 2007

12 Unique features of epigenetics
Epigenetics regulates when and which sets of genes are turned on and turned off in a specific cell type or organ It refers to features such as chromatin and DNA modifications that are stable over rounds of cell proliferation. The acquired characters can be transmitted to daughter cells or perhaps to the next generation It does not involve changes in the primary DNA sequence of the cell/organism and therefore is potentially reversible Tang WY and Ho SM Reviews in Endocrine & Metabolic Disorders 2007 Ho SM J. Allergies Clinical Immulogy 2010

13 Epigenetics- an emerging theory to explain individual variations in cancer risk
Epigenetics is the process by which the genotype of an organism interacts with the environment to produce its phenotype. It provides a framework to explain the source of variations in individual organisms and among populations Epigenetics explains why cells, tissues, and organs in an individual are different when every cell in the body are carrying identical genetic information. The differences are caused by the expression of different sets of genes in different cells in a distinct temporal sequence It also explains why members of a population or identical twins are different albeit the members/twins have very similar or identical genetic materials Tang WY and Ho SM Reviews in Endocrine & Metabolic Disorders 2007 Ho SM J. Allergies Clinical Immulogy 2010

14 Epigenetic mediation of normal differentiation - genes are compartmentalized into active (filled circles) and inactive (open circles) domains v morphogens

15 Epigenetic mediation of normal differentiation - genes are compartmentalized into active (filled circles) and inactive (open circles) domains v v v v v v v v v X X morphogens

16 Genetic polymorphisms
The epigenetics serves as an interface between the environment and the inherited genome Environmental factors ? Genetic polymorphisms ? Epigenetics

17 Relationship between genetics and epigenetics
Epigenetics are markings etched in the "margins" of one's genetic make-up Genome: static Epigenome: dynamic; subjected to changes including those brought on by environmental factors Tang WY and Ho SM Reviews in Endocrine & Metabolic Disorders 2007 Ho SM J. Allergies Clinical Immulogy 2010

18 Epigenetic affects gene expression leading to altered disease risk
There are at least three ways epigenetics work to affect gene expression : Non-coding RNAs, DNA methylation, and Histone modification These processes put genes in active and inactive compartments. Singularly or conjointly, they determine whether and when a gene or a set of genes is silenced or activated >> alter cell/organ functions A disruption of gene and protein expression by endogenous and exogenous factors are the bases of disease development Tang WY and Ho SM Reviews in Endocrine & Metabolic Disorders 2007 Ho SM J. Allergies Clinical Immulogy 2010

19 How does epigenetic work? - I
I. DNA Methylation Methylation is the attachment of methyl groups to regulatory regions of the DNA. Methyl groups Methyl groups

20 How does epigenetic work? - II
II. Histone Modification The double stranded DNA wraps around a group of proteins called the histones N-terminal tails of histones are often undergo covalent modifications : acetylation, methylation, phosphorylation and ubiquitination. These modified histone tails acts like “tags” marking regions of DNA as active (transcribale) or inactive (silenced or cannot be transcribed) into mRNA K= lysine; R= Arginine; S= Serine Histone methylation (Arginine): associate w/ HAT to form co-activator which mediates TF binding. Histone methylation (Lysine): Depend on which residue. K4H3: transcription activation; K9H3: transcription repression. Also, it often associates heterochromatin formation/ chromosome loss Histone phosphorylation: transcription activation by promoting acetylation of K14H3 and/or chromosome condensation. Histone ubiquitination (Lysine): is generally associated with increased gene expression. Exact mechanism is not fully understood. Daryl C. Drummond et al, 2004

21 Histone deacetylation
Active and inactive chromatin and gene regulation Active chromatin DNA Inactive chromatin Transcription H3 M TF A Silenced K9 K4 K27 Pol II Histone acetylation DNA demethylation Histone deacetylation DNA methylation HMTs HDACs DNMTs MBPs HATs DMEs HDMs Zhang X & Ho SM J. Mol Endocrinol 2010

22 Which factors affect epigenetics ?
Environmental factors, such as types and quantities of dietary fats, smoking, stress, and toxins may alter DNA methylation at sites important in health. Gene expression effects can be seen for at least three generations. Tang WY and Ho SM Reviews in Endocrine & Metabolic Disorders 2007 Ho SM J. Allergies Clinical Immulogy 2010; Zhang X & Ho SM J. Mol Endocrinol 2010

23 Can high fat diets promote breast cancer through epigenetics in adult life?

24 Published data from UC on the continuous high fat exposure model
Part I: Animal studies on Continuous high fat diets Samples collected at Day Day Day 100 DMBA* (In utero exposure)(pups with mothers) Tumor AIN, HFO,HFB, HFS AIN, HFO,HFB, HFS Breeding Birth Weaning High olive oil (HFO; primarily n-9 monounsaturated fatty acids) High butter (HFB; primarily saturated fatty acids) High safflower oil (HFS; primarily n-6 polyunsaturated fatty acids) DMBA induced DCIS and invasive adenocarcinoma

25 Continuous exposure to high fats diets stimulate mammary epithelial cell proliferation
AIN HFO Medvedovic et al 2009

26 Continuous exposure to high fat diets induces a unique cell proliferation gene signature in mammary epithelial cells Medvedovic et al 2009

27 Early origins of human diseases
Epidemiologic studies now support an early origin of adult human diseases. Classic examples include association between low birth weight and a greater risk of coronary heart disease, hypertension, stroke, depression, type 2 diabetes, and osteoporosis in later life Tang WY and Ho SM Reviews in Endocrine & Metabolic Disorders 2007 Ho SM J. Allergies Clinical Immulogy 2010; Zhang X & Ho SM J. Mol Endocrinol 2010

28 Developmental Plasticity- Windows of Susceptibility
Most human organ systems begin to develop early in gestation and do not become fully mature until weeks, months, or years after birth. A relatively long gestation and a period of postnatal and perhaps prepubertal maturation allow for prolonged interactions with the environment These include episodes of hypoxia; hypo- or hypernourishment; infection; and hormonal, drug, or toxin exposures. Developmental plasticity occurs when such exposures, during critical periods of maturation, result in permanent alterations in the structure or function of specific organ systems Tang WY and Ho SM Reviews in Endocrine & Metabolic Disorders 2007 Ho SM J. Allergies Clinical Immulogy 2010; Zhang X & Ho SM J. Mol Endocrinol 2010

29 Developmental reprogramming
It is a so-called adaptive trait since it is an attempt to establish phenotypes that meet the demands of later-life environment When the resulting phenotypes match the predicted later-life demands, the individual will remain healthy Tang WY and Ho SM Reviews in Endocrine & Metabolic Disorders 2007 Ho SM J. Allergies Clinical Immulogy 2010; Zhang X & Ho SM J. Mol Endocrinol 2010

30 Increased odds of a mismatch between early developmental programming and later-life demands
When there is a high degree of mismatch, however, one’s adaptability to adult life challenges will be impeded and disease risk will be elevated The latter scenario is more frequent today than in past decades since contemporary human life is greatly influenced by lifestyle choices, which often are in conflict with the programmed adaptive changes made during early development. Synthetic chemicals that mimic internal cues and artificial reproductive technologies are introduced into daily life at alarming rates. These can induce developmental reprogramming with no apparent late-life adaptive values. Tang WY and Ho SM Reviews in Endocrine & Metabolic Disorders 2007 Ho SM J. Allergies Clinical Immulogy 2010; Zhang X & Ho SM J. Mol Endocrinol 2010

31 Q; When? A: Early-life exposure
Q: What? A: High fat diets & pollutants Modified from Foley et al., 2008 Germline epimutation Genome-wide Demethylation Developmental epigenetic reprogramming Somatic epimutation Dysregulation of epigenetic process-> Disease development Environmental exposure Maternal Factors Diet and Lifestyle

32 Which factors affect epigenetics during early life through transplacental exposure ?
Next to smoking, diet is the most critical way to affect your offspring’s epigenomes are dietary fats.

33 In utero high fat diet exposure model
Part II: Animal studies on in utero exposure of high fat diets Samples collected at Day Day Day 100 DMBA* (In utero exposure) (pups with mothers) Tumor AIN, HFO,HFB, HFS AIN AIN Breeding Birth Weaning High olive oil (HFO; primarily n-9 monounsaturated fatty acids) High butter (HFB; primarily saturated fatty acids) High safflower oil (HFS; primarily n-6 polyunsaturated fatty acids) DMBA induced DCIS and invasive adenocarcinoma Ho SM et at unpublished 2010

34 In utero high fat exposure increases BCa tumor burden and volume in adult life
Ho SM et al unpublished 2010 * Different (p<.05) by Individual T-Test from HFO

35 Altered epigenome, gene expression
A new question to be addressed in our new grant - Combinational Effects between Diet and Toxicants ? Diet Genetics Environment Bisphenol A Dietary Fatty acids Leads to changes in cell behavior and morphology => Increased BCa risk Altered epigenome, gene expression and hormones In utero exposure Leptin Steroid hormones Adiponectin Adipokines

36 Which dietary components have protective effects?
For example, a young man who overeats gluttony likely has shorten the live of his sons and his grandsons through epigenetic effects.

37 Opportunities Identification of epigenetic biomarkers associated with early reprogramming of breast cancer risk Use these epigenetic biomarkers for the prediction of higher susceptibility and establish early surveillance (early detection) and intervention measures (diet and lifestyle modifications) Outreach and education; researcher and advocates working together

38 Looking Forward Diet is the second most important effector of our epigenetic modification known at this time. Its not just what we eat, but also how much. Epigenetic markers are long-lasting and hence are good warning signs. It is a new frontiers for us to control some aspects of our health. We can take charge of some aspects of our health but also affecting the health of our unborn children, growing children and their children.

39 RESEARCH PARTNERS COMMUNITY PARTNERS Presentations Publications
Shuk-mei Tracie Presentations Publications Conferences Education Liz Ricky Banita Mario Events Education Support Presentations Social media Newsletter Karen Linda Pattie Scott Marian Wendy S M Ho 2010

40 S M Ho 2010

41 S M Ho 2010

42 Acknowledgement UC Outreach Liaison Dr. Marian Miller Outreach Partner
Pink Ribbon Girls Ms. Tracie Metzger Ms. Benita Bailey Ms. Liz Kelly All members in Pink Ribbon Girls UC Science Team Dr. Shuk-mei Ho Dr. Scott Belcher Dr. Mario Medvedovic Dr. Ricky Leung Dr. Linda Levin Former UC members Dr. Bob Bornschein Dr. Marshall Anderson Ms .Robin Gear NIEHS 1U01ES S M Ho 2010


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