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The Biology
Biological Changes
in Breast Tissue during Pregnancy
When a female child approaches puberty,
she has only a few primitive Type 1 lobules in her breast
tissue. A rise in estrogen levels at the onset of puberty
leads to tissue growth by increasing the number of Type
1 lobules. Type 1 lobules consist of a cluster of approximately
11 small club-shaped end ductules, known as alveolar buds,
branched out from a terminal duct. The increase in hormonal
activity during puberty causes some Type 1 lobules to develop
into Type 2 lobules, in which the alveolar buds branching
from each terminal duct become smaller and multiply to an
average of 47 buds per terminal duct.(2)
The terminal ductal units of the Type 1 and 2 lobules are
known to be especially vulnerable to carcinogens, due to
their highly proliferative susceptability. (1,3-5)
In mid to late pregnancy, after at least 32 weeks gestation(6),
the alveolar buds of Type 2 lobules multiply and mature
into the grape-like pockets of cells, or alveoli, of Type
3 lobules. Type 3 lobules in turn differentiate into Type
4 lobules, which, after childbirth, secrete milk. Type 3
and 4 lobules, in which the tissues are fully differentiated,
are known to be resistant to carcinogens.(1,2,3,4,7,8)
As is well-known, and as stated by Valerie
Beral in her 2002 study, "pregnancies that result in
a birth are known to reduce a woman's long-term risk of
developing breast cancer"(9). The protection associated
with first full term pregnancy is due to differentiation
of the initially primitive ductal end cells into cancer
resistant milk producing lobules.(2-4,7,8,10-12)
Differentiation of breast tissue, which
occurs after 32 weeks, is a result of the interaction of
numerous hormones. After conception occurs, many hormones
including estrogens and progesterone prepare breast tissue
for lactation. Estrogen levels rise by 2000% in early pregnancy,
causing massive proliferation of Type 1 and 2 lobules, in
which mutations are more likely to arise.(3)
During normal pregnancy, the proliferative
effects of estrogen, prolactin hormone and growth factors
are balanced by the actions of other hormones such as human
chorionic gonadotropin hormone (hCG), as well as progesterone.(13)
hCG has a direct effect on the breast tissue by activating
inhibin, which regulates cell growth and induces the activation
of genes that control programmed cell death and differentiation.
Differentiation also occurs when hCG stimulates release
of progesterone.(14) Progesterone induces
a new set of chemicals within the breast cell that tell
it to stop dividing and mature into a cell that can produce
milk, but is no longer capable of replication.(15,16)
While estrogen primarily causes proliferation of breast
tissue, progesterone primarily causes differentiation.(27,32)
Differentiated Type 3 and 4 lobules are not only non-proliferative,
they also have a better ability to repair damage induced
in the DNA.(4,17)
Differentiation associated with full-term
pregnancy increases the overall number of Type 3 and 4 lobules.
Type 3 lobules remain as the predominant structure in childbearing
women until age 40. Thereafter, and especially after menopause,
Type 3 lobules mostly revert back to Type 1 lobules. The
breast tissue of a woman who has never become pregnant will
consist of mainly Type 1, some Type 2, very few Type 3,
and no Type 4 lobules.(18,19)
Without the profound rise of progesterone that occurs in
late pregnancy(20), few Type 1 and 2 lobules
will progress to the stage where progesterone stops cell
proliferation, controls programmed cell death, and differentiates
the lobules into cells that are better able to repair damage
to the DNA. Instead, they are left in the vulnerable state
in which carcinogens, including estrogen, (3,21-26)
can stimulate the uncontrolled growth of abnormal cells.
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Full-Term
Pregnancy versus Terminated Pregnancy
Pregnancy beyond at least 32 weeks causes
breast lobules to mature into highly differentiated tissue
that is resistant to carcinogens. When pregnancy is terminated
by induced abortion before full maturation of her breast
tissue, she is left with an increased number of the immature
Type 1 and 2 lobules, where cancers are more likely to arise.
This results in a greater net risk for breast cancer.
Pregnancy that is terminated by induced
abortion results in increased breast cancer risk in two
ways. First, estrogen stimulation in early pregnancy causes
massive proliferation of Type 1and 2 lobules, where cancers
can arise. If abortion terminates the pregnancy before 32
weeks, these lobules are not protected from cancer by progressive
maturation to Type 3 and 4 lobules, as they would have been,
had the pregnancy continued to term. So the woman is left
with a much greater number of cancer-vulnerable cells than
she had before she became pregnant. She is also left with
a much greater number of cancer-vulnerable cells than she
would have had if she had continued the pregnancy to term.
Secondly, this increased number of vulnerable
cells are exposed to extremely high levels of estrogen during
pregnancy, as well as during subsequent menstruation, which
can induce cancer cells to form. Without the balancing effect
of the marked progesterone rise of late pregnancy, estrogen
promotes the proliferation of both cancer vulnerable breast
tissue and existing tumors.(3,20)
Estrogen can even initiate cancers in susceptible women.(3,21-26)
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Estrogen
Exposure leads to Breast Cancer
Estrogen acts as a carcinogen in several
ways. In the first place, estrogen acts as a mitogen, stimulating
massive cell division through mitosis. Each time a cell
divides into two, it must replicate its DNA. When errors
or mutations occur during this process, abnormal cells can
result. Cells may lose the ability to stop dividing, or
may lose the information that controls programmed cell death.
Thus, by stimulating increased cell division, estrogen can
cause more abnormal cells to form. Timely exposure to progesterone
can stimulate the abnormal cells to either die off, or differentiate,
repair themselves, and control their proliferation before
they result in full blown cancer. Without progesterone exposure,
further estrogen stimulation also causes the abnormal cells
to multiply.(3,21-23)
Estrogen also acts as a genotoxin, or
mutagen, which directly attacks the DNA, causing mutations
and thus initiating a process that leads to the formation
of cancer cells. Along with stimulating cell division, estrogen
also activates the production of enzymes, which are required
to break down the estrogen and eliminate it from the body.
Some forms of estrogens are safely and easily excreted,
while others form unstable metabolites and by products that
can damage the DNA of cells.(7,20-28)
While estrogen can cause cancers to form by damaging DNA,
a full-term pregnancy results in more differentiated cells
that are better able to resist damage to the DNA as well
as better able to repair damaged DNA. Terminating a pregnancy
through induced abortion forfeits the protection afforded
by cell differentiation, as well as increasing exposure
of a greater number (than were present before onset of pregnancy)
of vulnerable cells to estrogen.
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Spontaneous
Abortion and Breast Cancer Risk
While induced abortion is associated with
increased estrogen exposure of vulnerable cells, early spontaneous
abortion generally is not. It has been shown that in pregnancies
ending in early spontaneous abortion, hormone levels are
generally not elevated to the same degree as in 'normal'
pregnancies.(29,30)
Thus, early spontaneous abortions do not result in increased
estrogen exposure with subsequently overall increased breast
cancer risk, as has been demonstrated in several studies.(31,1,32,40)
Because pregnancies that end in early spontaneous abortion
and induced abortion are physiologically unequal in regards
to hormone levels and estrogen exposure, studies examining
abortion and breast cancer risk should deal with induced
and early spontaneous abortion separately.
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Risk Factors
Related to Estrogen
It is well known that exposure to estrogen
increases breast cancer risk. In fact, most known risk factors
for breast cancer can be attributed to some form of excess
estrogen exposure, and/or exposure of highly vulnerable
Type 1 and 2 lobules to estrogen. Early (before age 12)
menarche, late (after 52) menopause, childlessness, late
first full-term pregnancy, use of hormone replacement therapy
after menopause , as well as the prolonged use of oral contraceptives
by young women, are well known risk factors of varying levels
of significance.(3,33-36)
In fact, the World Health Organization (WHO) reported in
its July 29, 2005 press release that a team of scientists
has determined that combined oral contraceptives (estrogen
plus progestogen) and combined menopausal therapy are "carcinogenic
to humans." Menopausal therapy was formerly classified
as "possibly carcinogenic to humans." It has been
upgraded to a Group 1 classification, "sufficient evidence
of carcinogenicity in humans." Oral contraceptives
received the same classification.(41)
The same biology that accounts for the known hormonal risk
factors for breast cancer mentioned above, also accounts
for the abortion breast cancer link.
Conversely, events that decrease estrogen
exposure decrease breast cancer risk: late menarche, early
menopause, early first full-term pregnancy (with its narrower
'window' of exposure of vulnerable cells to cyclic monthly
estrogen exposure, due to earlier differentiation of breast
tissue into cancer resistant cells), higher total parity,
and prolonged lactation.(3,4,36,37)
Valerie Beral and colleagues of the Collaborative Group
on Hormonal Factors in Breast Cancer have published a large
study on the effects of childbirth and lactation on breast
cancer risk. They concluded that, "It is estimated
that the cumulative incidence of breast cancer in developed
countries would be reduced by more than half, from 6.3 to
2.7 per 100 women by age 70, if women had the average number
of births and lifetime duration of breastfeeding that had
been prevalent in developing countries until recently. Breastfeeding
could account for almost two-thirds of this estimated reduction
in breast cancer incidence".(38)
Induced abortion obviously decreases both number of births,
as well as breastfeeding. Induced abortion, by causing loss
of the protective effects of both a full-term pregnancy
and breastfeeding, as well as increasing exposure of a greater
number of more vulnerable cells to estrogen, increases overall
breast cancer risk.
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References
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KE, Voigt LF, White E, Weiss NS. "Risk of Breast Cancer
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(15) Lee, et al. p. 129.
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Publishing Company 1993: 9,10. "The body makes three
principal forms of estrogen: estrone, estradiol, and estriol.
Estradiol, (in scientific terms, the word estrogen usually
refers specifically to a form of estradiol called 17-b estradiol)
the most potent, most plentiful estrogen, is secreted by
the ovaries, the testes, the placenta, and the cortex (outer
covering) of the adrenal glands…Estradiol is metabolized
in the liver, where it is converted to estrone, a much less
active estrogen, which is eventually excreted in the urine."
In this paper, "estrogen" generally refers to
estradiol.
(40) Kunz J , Keller PJ, "hCG, Oestradiol,
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Are Carcinogenic to Humans," World Health Organization
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