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Reproductive
Breast Cancer Risks
and
Breast Lobule
Maturation |
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. |
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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BREAST CANCER PREVENTION
INSTITUTE
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