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Fox Chase Cancer Center 2005 Scientific Report 1
Serum biomarkers and cancer risk. Dorgan,
in collaboration with Spittle, Weaver, Brinton,a
Chandlerb
We have conducted several prospective studiesof serum biomarkers
and breast cancer risk
based on the Columbia, MO Serum Bank.Some of our salient results
include positiveassociations of serum estrogen and androgenlevels
with subsequent breast cancer in post-menopausal women (Dorgan et
al., CancerEpidemiol. Biomark. Prev.5:533, 1996; Dorganet al.,
Cancer Epidemiol. Biomark. Prev.6:177,1997); inverse associations
of serum caro-tenoids with breast cancer risk (Dorgan et al.,Cancer
Causes Control9:89, 1998); and no asso-
ciation of pesticides and PCBs with breast cancerrisk (Dorgan et
al., Cancer Causes Control10:1,1999). More recently, we completed a
long-term follow-up of Columbia, MO Serum Bankparticipants. The
follow-up was highly suc-
cessful. Of the 6,720 women included in theextended follow-up,
6,154 (91.6%) werelocated; 566 (8%) were not locatable, 109
(2%)refused to participate, and 40 (
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Fox Chase Cancer Center 2005 Scientific Report 2
for 17OH-pregnenolone, and .95 for 17OH-progesterone. We
currently a re evaluatingvariation in serum levels of these
adrenalhormones over time in the same women.
We also are conducting a pilot study to eval-uate assay
reliability and within person varia-tion in Mllerian inhibiting
substance (MIS).
This hormone is secreted by the ovaries andhas been implicated
in breast and ovariancancer risk. The CV of the MIS assay was14.6%
and the ICC was .99 indicating thatassay variation is small
relative to between per-son variation in MIS levels. We currently
areevaluating variation in serum levels of MIS overtime in the same
women.
Childhood diet, serum hormones and breast
cancer susceptibility. Dorgan, in collaboration
with Barton,c Kwiterovich,
d
Lasser,
e
Stevens,
f
Robson,
g
Van Horn,
h
Snetselaar,
i
Shepherd,
j
Hilton,
j
Himes
k
Animal and ecologic studies strongly support arole of diet in
the etiology of breast cancer, butresults of case-control and
cohort studies areequivocal. Adolescence is a time of rapidgrowth
and maturation of the breasts, and awomans diet as an adolescent
may affect herrisk of developing breast cancer more than her
diet as an adult. Because of difficulties remem-bering exposures
in the distant past, there isconsiderable potential for
misclassification biasin case-control studies of adult breast
cancerthat attempt to evaluate recalled adolescentdiet. Cohort
studies begun today to evaluatethe effect of childhood and
adolescent diet onbreast cancer risk will not begin to yield
resultsfor 4050 years. Alternative strategies areclearly
needed.
The Dietary Intervention Study in Children(DISC) was a
multicenter, randomized con-trolled clinical trial that evaluated
the effect of areduced fat dietary intervention during pubertyon
serum sex hormones in 301 girls who werehealthy 810 year olds at
randomization. After5 years of participation, girls in the
interventiongroup had significantly 30% lower estradioland non-SHBG
bound estradiol, 21% lowerestrone, and 29% lower estrone sulfate
levels
during the follicular phase of their menstrualcycles compared to
girls in the usual caregroup. After 7 years, differences in
estrogenswere no longer apparent, but girls in the inter-vention
group had significantly 53% lower
luteal phase progesterone levels compared togirls in the usual
care group (Dorgan et al.,
J. Natl. Cancer Inst.
95
:132, 2003). These find-ings suggest that the DISC intervention
alteredfunction of the hypothalamic-pituitary-ovarian(HPO) axis.
Although it is currently unknownwhether these changes will
ultimately influ-
ence participants risk of developing breastcancer as adults,
estradiol and progesteroneare both breast mitogens that regulate
breastdevelopment during puberty. We currently areconducting a
long-term follow-up of DISCgirls, who are now in their twenties, to
evalu-ate the effect of the DISC intervention duringpuberty on
biomarkers associated with breastcancer risk, including serum
hormones, bonemineral density, and b reast density. This
unique opportunity
will greatly improve ourunderstanding of the effects of
adolescent dieton breast development and possibly the originsof
breast cancer.
Alcohol and breast cancer in postmenopausal
women.
Dorgan, in collaboration with Baer,
o
Albert,
a
Corle,
a
Judd,
o
Hartman,
p
Chandler,
b
Stanczyk,
q
Taylor
a
Alcohol ingestion is positively related to breastcancer risk in
most epidemiologic studies, butresults are inconsistent at lower
levels of intake,and a biological mechanism for the associationhas
not been established. We performed a con-trolled feeding study to
evaluate the effect ofchronic moderate alcohol ingestion on
serumlevels of hormones and other biomarkers. Par-ticipants
included 51 healthy postmenopausalwomen not using hormone
replacement ther-apy. Each participant consumed 15 gm alcohol/day,
30 gm alcohol/day, or a placebo beverage
during one of three 8-week dietary periods. Allfood and
beverages were supplied by the studyduring the dietary periods, and
energy intakewas adjusted to keep body weight constant.Hormones and
other biomarkers were mea-sured in serum collected at the end of
eachdietary period. When consuming 15 gm and30 gm alcohol/day,
respectively, participantsestrone sulfate concentrations increased
by7.5% and 10.7%, and their DHEAS concentra-
tions increased by 5.1% and 7.5% (Dorganet al.,J. Natl. Cancer
Inst.
93
:710, 2001). Noneof the other hormones measured changed
sig-nificantly. Women with elevated levels ofestrone sulfate and
DHEAS are at an increased
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Fox Chase Cancer Center 2005 Scientific Report
3
risk of breast cancer, and these results suggest amechanism by
which consumption of 1 to 2alcoholic drinks/day by
postmenopausalwomen could increase their breast cancer risk.
Heavier postmenopausal women are at anincreased risk of breast
cancer, and alcoholcould also potentially influence breast
cancer
risk through effects on energy balance. Leptin isinvolved in
energy balance and has beenhypothesized to play a role in
carcinogenesis.
We found that alcohol ingest ion increasesserum leptin levels in
postmenopausal women(Roth et al., J. Natl. Cancer Inst .
95
:1722,2003). When consuming 15 gm and 30 gmalcohol/day,
respectively, participants leptinlevels rose by 7.3% and 8.9%
compared to con-suming no alcohol. Alcohol ingestion could
further increase breast cancer risk by increasingoxidative
stress (1). When consuming 30 gmalcohol/day, participants serum
-tocopheroldecreased by 4.6%, while their isoprostane
levelsincreased by 4.9%.
Folate and vitamin B
12
are required for DNAmethylation and nucleotide synthesis.
Effectson these vitamins could potentially mediate theassociation
of alcohol on breast cancer risk.Lower levels of folate and vitamin
B
12
amongheavy drinkers are well established, but effectsof moderate
drinking are less clear. In ourstudy (Laufer et al., Eur. J. Clin.
Nutr.
8
:1518,2004), consumption of 30 gm alcohol/day
resulted in a significant 5% decrease in vitaminB
12. However, methylmalonic acid, a sensitivefunctional indicator
of vitamin B
12 status, wasunchanged. Serum folate levels also were
notchanged significantly when consuming 1530 gm alcohol/day,
although homocysteinelevels increased significantly by 3% when
women consumed 30 gm alcohol/day.Increased concentrations of
insulin-like
growth factor-I (IGF-I) and decreased concen-trations of its
principal binding protein (IGFBP-3) have been associated with
cancer at severalsites. Although observational studies suggest
apotential effect of alcohol on levels of IGF-1and IGFBP-3,
controlled feeding studies havenot been conducted previously. We
found thatconsumption of 15 gm alcohol/day did not
affect serum IGF-I concentrations but signifi-cantly increased
IGFBP-3 levels, whereas con-sumption of 30 gm alcohol/day
significantlydecreased IGF-I concentrations but did notchange
IGFBP-3 levels (2).
Alcohol ingestion could increase cancer risk viaoxidative DNA
damage. In our study however,alcohol ingestion did not increase
oxidative DNAdamage measured by 5-hydroxymethyl-2-deox-yuridine
(5-HMdU) autoantibodies in serum (3).Eight weeks may be too short
an interval toobserve measurable differences in oxidative DNAdamage
measured by 5-HMdU. Future studieswill use a panel of biomarkers of
DNA damage.
Publications
1.
Hartman, T.J., Baer, D.J., Graham, L.B., Stone, W.L., Gunter,
E.W., Parker, C.E., Albert, P.S., Dorgan, J.F.,Clevidence, B.A.,
Campbell, W.S., Tomer, K.B., Judd, J.T., Taylor, P.R. Moderate
alcohol consumption and levels ofantioxidant vitamins and
isoprostanes in postmenopausal women. Eur. J. Clin. Nutr. 59
:161-168, 2005.
2.
Lavigne, J.A., Baer, D.J., Wimbrow, H.H., Albert, P.S., Brown,
E.D., Judd, J.T., Campbell, W.S., Giffen, C.A.,Dorgan, J.F.,
Hartman, T.J., Barrett, J.C., Hursting,, S.D., Taylor, P.R. Effects
of alcohol on insulin-like growthfactor-I and insulin-like growth
factor binding protein-3 in postmenopausal women. Am. J. Clin.
Nutr.
81
:503-507, 2005.
3.
Mahabir, S., Baer, D.J., Johnson, L.L., Frenkel, K., Dorgan,
J.F., Campbell, W., Hartman, T.J., Clevidence, B.,Albanes, D.,
Judd, J.T., Taylor, P.R. No association between alcohol
supplementation and autoantibodies to DNAdamage in postmenopausal
women in a controlled feeding study. Eur. J. Cancer Prev. 14
:427-429, 2005.
Fox Chase researcher
a
L.A. Brinton, P. Albert, D. Corle, P.R. Taylor: National Cancer
Institute, Bethesda, MD
b
D.W. Chandler: Esoterix Endocrinology, Calabasas Hills, CA
c
B.A. Barton: Maryland Medical Research Institute, Baltimore,
MD
d
P.J. Kwiterovich: Johns Hopkins University, Baltimore, MD
e
N.L. Lasser: New Jersey Medical School, Newark, NJ
f
V.J. Stevens: Kaiser Permanente Center for Health Research,
Portland, OR
g
A.M. Robson: Childrens Hospital, New Orleans, LA
h
L. Van Horn: Northwestern University Medical School, Chicago,
IL
i
L. Snetselaar, R.M. Lauer: University of Iowa, Iowa City, IO
j
J. Shepherd, N. Hilton: University of San Francisco, San
Francisco, CA
