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Reproductive
Breast Cancer Risks
and
Breast Lobule Maturation
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Breast maturity is closely correlated with known reproductive
risk factors for breast cancer. The breast is not fully
developed at birth. At full development, the breast is
comprised of 15- 25 lobes or segments which are in turn
comprised of lobules. Lobules in turn are composed of
breast cells.
There are 4 types of lobules whose structural
differences appear under the microscope.
These lobules represent different stages of development
and maturity of breast tissue.
Type 1, 2 & 3 lobules are differentiated by the average
number of ductules per lobular unit:
Type 1 has 11; Type 2 has 47; Type 3 has
80.
Type 4 lobules are fully matured and contain colostrum
or milk.
Type 1 lobules mature into Type 2 lobules under the cyclic
influence of the female hormones, estrogen and progesterone,
during menstrual cycles.
Type 2 lobules only become fully mature into Type 3 then
Type 4 lobules under the influence of the hormonal changes
of a full-term pregnancy.
A major influence in this final stage of maturation into
Type 4 lobules is human placental lactogen (hPL) which
sharply rises during the last few months of pregnancy.
Human chorionic gonadotropin (hCG, which stimulates the
ovaries to produce estrogen and progesterone within a
few days after conception) and prolactin also play a major
role in maturation. HCG and hPL are made in the mother's
womb during pregnancy. HCG also stimulates the ovary to
produce inhibin, a cancer suppressing hormone, increasing
protection of the mother even more.
Actual photomicrographs
of human breast lobules:
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| Type 1 Lobue |
Type 3 Lobule |
These 4 types of lobules are also metabolically
different and have different breast cancer potential.
Type 1 & 2 lobules have more estrogen and progesterone
receptors than Type 3 which cause them to grow through
mitosis (cell division) when estrogen and progesterone
levels are elevated. Mitosis requires replication of DNA
(genes) and therefore can result in mutations.
Mutated cells also undergo mitosis. Multiple mutations
can cause cancer cells to form. Cells of Type 1 &
2 lobules also multiply faster than Type 3 resulting in
more chances for mutations to occur. This growth (proliferation)
under estrogen and progesterone stimulation explains the
cancer causing properties of estrogen/progestin combination
drugs.
Type 1 lobules are where
ductal cancers start. These
account for at least 85% of all breast cancers.
Type 2 lobules are where
lobular cancers start. These account for about
12% of all breast cancers.
Type 3 lobules are cancer
resistant when they are the result of the regression of
Type 4 lobules after birth
and weaning.
Type 4 lobules are cancer
resistant.
The breast maturation process through a normal full-term
pregnancy
At birth, after the mother's
hormones dissipate, a small amount of breast tissue lies
dormant under the infant's nipple & areola.
At puberty, when the ovaries
produce cyclic elevations of the female sex steroid hormones,
estrogen and progesterone, the breast enlarges. However,
only Type 1 and 2 lobules are formed, which are where
ductal and lobular cancers start respectively. Most of
the breast tissue is stroma (tissue surrounding the lobules).
The lobules account for about 10% of the breast tissue.
After puberty, there is
a reduction in stroma and lobules account for 30% of the
breast tissue: 75% are Type 1 and 25% are Type 2 lobules
with a few Type 3.
After conception, the
baby secretes hCG, stimulating the ovaries to produce
the pregnancy hormones estrogen and progesterone, which
cause the breast to start to enlarge by making greater
numbers of lobules. This causes the mother's breast
to feel sore and tender.
By the end of the 1st trimester,
during the maturation of Type 1 lobules into Type 2, the
actual numbers of these lobules
will increase while the surrounding tissue (stroma)
decreases. The breast now has more
places for cancers to start.
By mid 2nd trimester, the
breast has doubled in volume
and has continued to mature rapidly under the influence
of placental lactogen. The breast is now 70% Type 4 cancer
resistant lobules and 30% immature cancer susceptible
lobules.
By the end of the 3rd trimester,
85% of the breast is fully matured to Type 4 lobules and
only 15% remain immature cancer susceptible lobules, leaving
fewer places for cancer to start.
At delivery, the mother's
breasts are now predominantly
Type 4 lobules. They are fully mature and resistant
to carcinogens, resulting in lower
long-term risk of breast cancer for the mother.
While breastfeeding, the
mother's menstrual cycles may stop or become anovulatory,
further reducing her risk.
After weaning, Type 4 lobules
regress to Type 3 and the breasts get smaller again. However,
there is evidence of permanent
changes in the genes of these Type 3 lobules which
confer life-long cancer resistance
even after menopause when they further regress to Type
1.
| The "susceptibility window," the period
between puberty and a full-term pregnancy, is the
time the breast is most susceptible to forming cancer;
i.e., when the woman's breast is composed primarily
of Type 1 and 2 lobules. |
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These facts of the breast maturation
process account for the following known facts
about breast cancer risk:
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A woman who has a full-term pregnancy
decreases her breast cancer risk. A woman
who is childless has increased breast
cancer risk.
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The timing of pregnancy in the course
of a woman's reproductive life is crucial
to breast cancer risk.
The longer a woman waits before having
her first child, the higher her risk because
she has a longer "susceptibility
window." For example, a woman who
gives birth at 18 has a 50-75% lower risk
of breast cancer than a woman who waits
until she is 30.
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Each additional birth results in a further
10% risk reduction. Breast feeding reduces
risk in proportion to the cumulative length
of lactation.
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Women who have breast cancer despite
prior full-term childbirth, have a higher
percentage of Type 1 lobules than women
who give birth and do not develop cancer.
This is possibly due to a defect in maturation.
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Scientists have
been unsuccessful to date in their attempt
to create an hormonal "cocktail"
to protect childless women from breast cancer.
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Illustrations of pregnancy outcomes and their
effect on breast cancer risk
| Before and
After…First full-term pregnancy (FFTP): |
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Full-term births
cause near complete maturation
of the breast to Type 4 lobules therefore
lowering breast
cancer risk. A pregnancy ending
between 32 and 36 weeks has about 90%
of the protective effect of a full-term
pregnancy of 40 weeks. If the first full-term
pregnancy occurs late in the woman's reproductive
life, her risk is transiently elevated
in the first few years post partum. This
is due to mutated cells that may have
formed during a long "susceptibility
window," which then may become cancerous.
Cancer cells already present at conception
may grow faster under the stimulation
of the elevated pregnancy hormones estrogen
and progesterone.
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| Before and
After...Spontaneous abortion (miscarriage)
in the 1st Trimester: |
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Approximately 23% of all conceptions
end in a spontaneous abortion by 11 weeks
in the 1st trimester. This is when the
fetus and placenta must make enough hormones
to sustain the pregnancy. In
most pregnancies which miscarry during
the 1st trimester, pregnancy hormones
are lower than in a normal pregnancy,
due to either a fetal or ovarian abnormality.
Therefore, the breasts may have never
grown more Type 1 & 2 lobules (places
where cancers start) in response to the
pregnancy or at least very few. This is
why women who miscarry will often remark
they never "felt" pregnant before
the miscarriage. Their breasts were never
sore from growing and they were never
nauseous from higher than normal hormone
levels. Thus the
vast majority of spontaneous abortions
(miscarriages) in the 1st trimester do
not increase breast cancer risk.
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| Before and
After...Induced abortion in the 1st Trimester: |
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Induced abortion of a normal
pregnancy during which there has
been breast growth results in increased
risk of breast cancer in the mother. The
later in pregnancy an abortion is done,
the higher the risk of breast cancer as
the more Type 1 and 2 lobules will have
formed. Induced
abortion leaves a woman with more places
for breast cancer to start. If
an induced abortion is done on a pregnancy
which would have spontaneously aborted
by 11 weeks, there would be no
increase in risk. There is some data to
suggest that the sooner a woman delivers
and nurses a child after having had a
prior induced abortion, the smaller the
risk increase from the abortion.
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Other pregnancy outcomes and breast cancer risk
Premature delivery before
32 weeks:
Premature delivery before 32 weeks is known
to more than double breast cancer risk because
it leaves the breast with
more places for cancers to start. The
risk is proportional to gestational length.
The pregnancy hormone levels are usually normal
so the breast changes are those of a normal
pregnancy. The effect of premature delivery
is the same as in an induced abortion as they
differ only in whether the fetus is delivered
alive or not. The premature delivery may be
caused by multiple gestations (twins, triplets
or more with assisted reproduction pregnancies),
an incompetent cervix, an induced abortion,
or physician-induced labor for fetal abnormalities
such as anencephaly.
Spontaneous abortion
(miscarriage) in the 2nd Trimester:
The effect would probably be the same as a premature
delivery in the second trimester and increase
risk. Most 2nd trimester spontaneous abortions
occur because of a physical and not hormonal
abnormality. For example, there is fetal demise
or the mother sustained an injury.
Induced abortion in
the 2nd Trimester:
The effect would be the same as a premature
delivery before 32 weeks and a spontaneous abortion
in the 2nd Trimester. There would be increased
risk because there are more
places for cancers to start. There are
data to show there is a 3% increase in breast
cancer risk for each week of gestation before
the abortion.
Stillbirth:
The death of an infant near or at delivery would
not change that full-term pregnancy's protective
effect on the breast. There would have been
normal maturation of the breast to Type 4 cancer
resistant lobules.
Ectopic Pregnancy:
This is the result of an embryo which grows
outside of the womb (uterus); e.g. in the mother's
Fallopian tube. Its effect on breast cancer
risk would most likely be small or minimal as
the pregnancy usually ruptures or causes a medical
emergency very early on in the pregnancy. There
is too little data to be certain of any small
risk elevation.
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References
1. Harris JR. Diseases of the breast, 2nd ed. Lippincott
Williams & Wilkins 2000. (Ch1. Breast anatomy and
development; Ch.2. Biochemical control of breast development).·
A woman who has a full-term pregnancy decreases her breast
cancer risk. A woman who is childless has increased breast
cancer risk.
2. Bland IE, Copeland, EM. The Breast: Comprehensive management
of benign and malignant diseases, 3rd ed. Saunders 2004.
(Ch.3. Breast physiology: normal and abnormal development
and function).
3. Blackwell RE, Grotting JC. Diagnosis and management
of breast disease. Blackwell Science 1996. (Ch.2. Breast
dysfunction: galactorrhea and mastalgia).
4. Russo J, et al. Development of the Human Mammary Gland.
in The Mammary Gland, ed. M Neville, et al. Plenum Publishing
Corp 1987;67-93.
5. Daling JR, et al. Risk of breast cancer among young
women: relationship to induced abortion. J Natl Cancer
Institute 1994;86:1584-1592.
6. Melbye M, et al. Preterm delivery and risk of breast
cancer. Br J Cancer 1999;80:609-13.
7. Russo J, et al. Developmental, cellular, and molecular
basis of human breast cancer. J Natl Cancer Institute
Monographs. No. 27, 2000;17-37.
8. Russo J, et al. Mammary gland architecture as a determining
factor in the susceptibility of the human breast to cancer.
The Breast J 2001;7:278-291.
9. Russo J, et al. Cancer risk related to mammary gland
structure and development. Microscopy Research and Technique
2001;52:204-233.
10. Vatten LJ, et al. Pregnancy related protection against
breast cancer depends on length of gestation. Br J Cancer
2002;87:289-90.
11. Hsieh C, et al. Delivery of premature newborns and
maternal breast cancer risk. Lancet 1999;353:1239.
12. Rooney B, et al. Induced abortion and risk of later
premature births. J Am Phys Surgs 2003;8:46-49.
13. Behrman R, et al. Preterm birth: Causes, consequences
and prevention. Institute of Medicine 2006, page 519 Appendix
B, Table 5.
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Ordering information
BREAST CANCER PREVENTION INSTITUTE
515 Church Street, Suite 1, Bound Brook, NJ 08805 USA
Call toll-free: 1-86-NO CANCER (1-866-622-6237)
E-Mail: info@bcpinstitute.org
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