BREAST CANCER

BREAST the mammary gland is more prone to b attacked by cancer..
breast cancer attacks the lymph nodes of the breast mailnly the axillary group of lymph nodes
breast cancer over the skin appears like PEAU DE ORANGE.
surgically breast cancer is of 3 types
1.due to infection

2.a beningn tumour which is treated by EXISION

3.a malignant tumour which needs mastectomy ( recently i did an MRM{MODIFIED RADICAL MASTECTOMY}

other important method is PATTYs mastectomy

BREAST CANCER CAN BE IDENTIFIED BY A MAMMOGRAPHY..

it is a must needed investigation for present day women to do this test and safe guard themselves from BREAST CANCER

DNA MICRO ARRAY AND BREAST CANCER

DNA Microarray and Breast Cancer


Microarray is a powerful tool used widely to characterize tumors and has greatly improved
the ability to subclassify tumors according to shared molecular characteristics and clinical behavior.
It is a method to measure the expression of a large number of genes in any specimen simultaneously.
Researchers at Stanford University were the first to describe and use DNA microarray to study gene
expression in various diseases including cancer. Breast cancer is the second most common cancer
among Indian women. Multiple factors like age, diet, obesity, parity, age at first childbirth, oral
contraceptives, exogenous estrogens, genetics, environment, geographic location influence the
development of this heterogeneous disease. Gene expression in these cancers by microarray is fast
gaining in popularity in providing better prognostic and predictive information on the disease. This
review is an attempt to look at the recent advances in breast cancer research with DNA microarray TECHNOLOGY

WHOLE GENOMIC APPROACH IN BREAST CANCER

current methods of classification of breast cancer are based
on clinical stage, histopathological characteristics and few
immunohistochemical markers. These traditional methods
are often subjective, inconsistent and do not have the ability to differentiate subtle differences that may be of importance
for developing a better understanding of the tumor and
advancing therapeutic strategies for treatment. For example,
to identify breast cancer patients who need to be
administered adjuvant systemic therapy, the criteria
followed are a combination of age, tumor size, axillary node
status, and histopathological grade and hormonal status of
the tumor. However, these criteria do not predict disease
progression and clinical outcome precisely. This uncertainty
sometimes results in patients who need adjuvant therapy
not receiving it, while some are treated unnecessarily,
thereby being exposed to the risk of side effects. Expression
profiling of thousands of genes simultaneously using DNA
microarrays has a great potential to sub-classify tumors,
which are indistinguishable with current criteria, to different
groups so that the outcome to therapy can be predicted
more precisely [39••]. Although individual gene variations
may exert major effects on drug response, this response is
often a complex trait with several polymorphic genes and
other environmental factors contributing to different
degrees to overall treatment outcome. A number of studies
have reported the gene expression profiling of breast cancer,
and those of particular relevance to pharmacogenomics are
discussed below [40••,41-46,47••,48,49••,50••,51••].
Expression profiling can be used to define subtypes of breast
cancer more precisely. Approximately 60% of breast cancer
cases are ER positive (ER+), which is a well recognized
prognostic and predictive factor in early breast cancer.
Women with ER+ status respond better to hormonal or anti-
estrogen (such as tamoxifen) therapy. However, the
immunohistochemical method for determining ER status
often produces false results. For example, alterations in the
genes involved in ER signaling pathways leading to
defective ER pathways cannot be differentiated by the above
method. Gruvberger et al have identified the 100 most
important ER discriminator genes to demonstrate that ER+
and ER negative (ER-) tumors display remarkably different
phenotypes, which they attributed to their evolution from
distinct cell lineages [40••]. Unexpectedly, only a few of the
ER discriminator genes appear to be part of the ER signaling
pathway, suggesting that the difference in gene expression
profile between ER+ and ER- tumors can only partly be
explained by the activity of a functional ER pathway in ER+
tumors. Another independent study by West et al identified
a specific expression of a set of genes, which included not
only ER and ER pathway genes, but also genes that encode
proteins that synergize with ER, such as HNF3α and the
androgen receptor, to identify the ER status [51••]. This
study also identified a gene expression pattern to categorize
lymph node status. A study by Sørlie et al [47••] refined the
previously defined subtypes of breast tumors [44,46]. A total
of 115 malignant breast tumors were analyzed by
hierarchical clustering based on patterns of expression of 534
'intrinsic' genes and were subdivided into five subgroups,
some of which were previously known and some of which
are new entities.
Microarray-based expression profiling can also identify
expression patterns of a small set of markers that can predict
the outcome in a patient with a tumor or response of a
patient to a specific therapy. Landmark studies by van de vijvar et al revealed two genetic signatures, one correlated
with a good prognosis and the other with a poor prognosis,
based on the overall survival and development of distant
metastasis [50••,49••]. In their first study, oligonucleotide
microarrays containing 25,000 genes were used to study the
expression patterns of 98 primary tumors from young
patients under the age of 55 years with lymph node-negative
type cancer [49••]. Supervised clustering using information
about the clinical outcome in these patients identified a set
of 70 genes with an expression pattern that allowed highly
accurate classification of the patients into those with a poor
prognosis and those with good prognosis. A limitation of
this study was that patients with a known outcome were
used. To provide a more accurate estimate of the risks of
metastasis associated with the two gene expression patterns,
and to substantiate that the gene expression profile of breast
cancer is a clinically meaningful tool, van de Vijver et al
studied a cohort of 295 patients with either lymph node-
negative or lymph node-positive breast cancer [50••].
Examination of the expression levels of the previously
identified 70 predictor genes allowed the classification of 115
patients to the good-prognosis category and 180 patients to
the poor-prognosis category. Interestingly, the prognosis
profile did not appear to depend on lymph node status, as
patients with node-negative and node-positive status were
uniformly present in both categories. However, the
molecular profiling-based classification correlated well with
the age of the patient, histological grade and ER status of the
tumor. The prognosis profile predicted both the survival
and the risk of distant metastases. The overall ten-year
survival rate was 94.5% in the good-prognosis group and
54.6% in the poor-prognosis group. The probability of
remaining free of distant metastases at ten years was 85.2%
in the good-prognosis group and 50.6% in the poor-
prognosis group. A major implication of this study is that
molecular signature-based prediction of clinical outcome is
better than any of the currently used criteria

PHARMACOGENETICS AND BREAST PART 2

mutation in the cell cycle-checkpoint kinase gene (CHEK2) confer a small but
appreciably enhanced risk of breast cancer [16••]. CHEK2
encodes a cell-cycle checkpoint kinase and is implicated in
DNA repair processes involving BRCA1 and p53. The
1100delC mutation, a truncating variant of CHEK2 that
abrogates the kinase activity, occurs at a frequency of 1.1%
in healthy individuals. However, this variant is present in
5.1% of individuals with breast cancer families that do not
carry mutations in BRCA1 or BRCA2. This mutation results
in an approximately 2-fold increase of breast cancer risk in
women and a 10-fold increase of risk in men. In contrast, the
variant confers no increased cancer risk in carriers of BRCA1
or BRCA2 mutations.
The penetrance of BRCA1/BRCA2 mutations is modified by
other genetic and/or environmental factors. Identification of
such modifiers would help in facilitating more accurate risk
assessment in carriers who face difficult clinical choices
regarding prophylactic mastectomy and oophorectomy.
Candidate modifiers include genes with products that are
known to interact with BRCA1 and BRCA2 [17]. RAD51 is a
homolog of bacterial RecA, which is required for meiotic
and mitotic recombination and for recombinational repair of
double-strand DNA breaks. Both BRCA1 and BRCA2
interact with RAD51 [18,19]. The presence of an SNP in the
5'-untranslated region of RAD51 (135 G-C) increased breast
cancer risk by 4-fold among BRCA2 but not BRCA1 mutation
carriers [20•,21•]. It is possible that this SNP could affect the
mRNA stability and/or translation efficiency, leading to
altered RAD51 protein levels. The differential effect of
RAD51 polymorphism on BRCA1 versus BRCA2 mutation
carriers may relate to the different pathways by which
BRCA proteins function.
Predicting drug efficacy and toxicity
The study of large numbers of genes that influence drug
activity, toxicity and metabolism provides the opportunity
to customize drug treatments, thereby eliminating the
uncertainties of current cancer chemotherapy. Specifically,
genetic polymorphisms in genes responsible for metabolism
and disposition of drugs, transporters and targets of drugs
are being explored [22••].
The cytochrome P450 (CYP) system has been under study
for a considerable period of time for predicting drug
efficacy. CYP enzymes are members of a multiple gene
'superfamily'. These enzymes play an important role in
steroidogenesis and detoxification of xenobiotics, such as
polycyclic aromatic hydrocarbons, benzopyrene, arylamines
and heterocyclic amines. One CYP gene, CYP2D6, appears to
contribute to metabolism of many anticancer agents [23]. It
is believed that common SNPs in CYP2D6 impair the
activity of CYP2D6 and perhaps alter the pharmacokinetics
of anticancer drugs.
Glutathione S-transferases (GSTs) detoxify a variety of
carcinogens and cytotoxic drugs by catalyzing the
conjugation of a glutathione moiety to the substrate.
Individuals who are homozygous carriers of deletions in the
GSTM1, GSTT1 or GSTP1 genes may have a higher risk of
cancer of the breast and other sites due to their impaired
ability to metabolize and eliminate carcinogens
Most drugs interact with specific target proteins, such as
receptors, enzymes or proteins involved in, for example,
signal transduction and cell cycle control, for exerting their
effects. Polymorphisms in thee target genes can alter
sensitivity to the drugs. This interaction has been exploited
in the analysis of breast cancers to determine their suitability
for treatment with the recombinant humanized monoclonal
antibody trastuzumab (Herceptin) [27••], which brings
about the death of breast cancer cells by binding to HER2
receptors on their surface. The HER2 proto-oncogene
encodes a 185-kDa cell surface human epidermal growth
receptor 2 protein known as the HER2 protein or receptor
[28]. The gene is also known as HER2/neu, as it has
homology to the rat gene neu. Normal cells express a small
amount of HER2 protein, which is activated by
heterodimerization with HER1, HER3 and HER4 in a
complex with their ligands [29]. The HER2 gene is amplified
in 25 to 30% of breast cancers, leading to the expression of
HER2 proteins at abnormally high levels in cancer cells [30].
Women with breast cancers that overexpress HER2 have an
aggressive form of the disease with significantly shortened
disease-free survival and overall survival [29,31-33].
Treatment with trastuzumab is successful only in breast
cancers that overexpress HER2 receptor.
Fluoropyrimidine prodrugs (eg, capecitabine) are widely
used to treat solid tumors such as colorectal, breast, and
head and neck cancer. This drug needs to be activated in the
tumor to the active drug 5-fluorouracil (5-FU) by the enzyme
thymidine phosphorylase (TP), which is usually expressed
in higher amounts in tumors than in healthy tissue.
Normally,
85%
of
5-FU
is
broken
down
by
dihydropyrimidine dehydrogenase (DPD) in the liver, but
between 3 to 5% of the population have reduced DPD
activity and manifest more severe gastrointestinal and
hematological toxicity when treated with 5-FU. Reduced
DPD activity has been correlated to mutational inactivation
[34]. The ratio of TP to DPD expression (TP/DPD ratio)
appears to determine the level of 5-FU in the tumor, in
addition to its effectiveness. 5-FU inhibits tumor cell
proliferation by targeting thymidylate synthase (TS), an
enzyme that is required for de novo pyrimidine synthesis.
Multiple studies have demonstrated that TS mRNA and
protein levels are inversely related to clinical antitumor
response [35,36]. The expression of TS is controlled in part
by a polymorphism characterized by a multiple number of
tandem repeats of a 29-base pair sequence in the 5'-promoter
enhancer region (TSER) of the gene. Multiple in vivo studies
have demonstrated that increasing the number of repeats
leads to an increase in TS mRNA and protein levels
[37•,38•]. Together, these studies suggest that combined
genotyping and protein level estimation of TP, DPD and TS
genes might be useful in selecting patients who are likely to
tolerate and respond to 5-FU therapy.

PHARMACOGENETICS AND BREAST PART 1

PHARMACOGENETICS AND BREAST PART 1

Pharmacogenomics is the study of genetic variations between
individuals to predict the risk of toxic side effects and the probability
that a patient will respond to single- or multidrug chemotherapy.
Breast cancer remains one of the most common cancers among
women worldwide and is second only to lung cancer in cancer-
related death. A better understanding of the mechanisms of
initiation and progression of breast cancer is needed for early
diagnosis and development of better therapeutic methodologies.
Differences in cancer patients' responses to chemotherapy have often
been attributed to pathogenesis and severity of the disease, drug
interactions, patient's age, gender, nutritional status, organ
functions and tumor biology. It is now well recognized that genetic
variations in drug target genes, disease pathway genes and drug
metabolizing enzymes can have greater influence on drug efficacy
and toxicity. In addition, germline variants can be used to study
breast cancer susceptibility, as well as the variable response to both
drug and radiation therapy used in the treatment of breast cancer.
This review discusses clinically relevant individual gene variations
that influence breast cancer susceptibility and cancer therapy, as
well as the microarray-based expression profiling studies that have
great potential in cancer pharmacogenomics in terms of tumor
classification, drug and biomarker discovery and drug efficacY

Pharmacogenomics and single nucleotide
polymorphisms
Pharmacogenomics is the study of how genetic variations
influence responses to drugs. Genetic variations in drug-
metabolizing enzymes, transporters, receptors and other
drug targets have significant effects on the efficacy and
toxicity of many drugs. Pharmacogenomics combines
traditional pharmaceutical sciences such as biochemistry
with annotated knowledge of genes, proteins and single
nucleotide polymorphisms (SNPs). It is believed that drugs
might one day be tailor-made and adapted to each
individual's genetic makeup. Although factors such as
environment, diet, age, lifestyle and state of health can
influence an individual's response to medicines, their
genetic make-up is the key to creating personalized drugs
with greater efficacy and safety.
SNPs are the most frequently found DNA sequence
variations in the human genome, compared with infrequent
variants (mutations), the primary cause of genetic disorders.
It is believed that SNPs may contribute significantly to
genetic risk for common diseases [4••]. It is estimated that
the average nucleotide diversity is 1 difference/1200
basepairs. Approximately 1 million SNPs are likely to occur
in human genes, with approximately 500,000 being non-
coding SNPs, 200,000 being silent coding SNPs and 200,000
being replacement coding SNPs [5]. SNPs found in the
coding and regulatory regions of genes are likely to be the
most relevant variants. Efforts to identify all SNPs and their
relevance to disease (cancer) susceptibility and treatment
outcome are continuous, and may take several more years.
However, the approach taken by many scientists at present
is the candidate gene approach in which one examines the
SNPs of the chosen gene that are likely to have an effect.
Single gene variations in pharmacogenomics
Single gene variation studies of both SNPs and mutations
are of use in predicting the risk of cancer development and
predicting drug efficacy and toxicity.
Predicting the risk of developing breast cancer
The lifetime risk of a woman developing breast cancer is
approximately 10% [1]. Approximately, 5 to 10% of breast
cancers are of hereditary origin and two major genes
associated with hereditary breast and ovarian cancer, breast
cancer susceptibility gene 1 (BRCA1) and breast cancer
susceptibility gene 2 (BRCA2), have been identified [6••,7••].
Mutations in either of these genes confer a lifetime risk of
developing breast cancer of between 60 and 85% [8].
However, mutations in these genes account for
approximately 40% of hereditary breast cancer and only 2 to
3% of all breast cancer. Additional breast cancer
susceptibility genes with high-penetrance alleles are
believed to exist [9,10•]. Breast cancer also occurs in a
number of multicancer syndromes, such as Li-Fraumeni
syndrome, Li-Fraumeni-like syndrome, Cowdens syndrome,
Peutz-Jeghers syndrome and Muir-Torre syndrome, in
which affected individuals inherit mutations in p53, hCHK2,
PTEN, STK11/LKB1 and MSH2/MLH1, respectively [11-15].
Studies of BRCA1 and BRCA2 signaling pathways are
discovering newer genes that also appear to play important
roles in breast cancer susceptibility.

MILK EJECTION

ejection is critical for successful lactation, because
only small volumes of milk (1–10 mL) can be either
expressed
46
or removed by the breastfeeding infant
40
before milk ejection. Failure to remove sufficient quan-
tities of milk results in a decrease in milk production
because of local control mechanisms.
47
Stimulation of
the nipple initiates milk ejection via initiation of nervous
impulses to the hypothalamus, which stimulates the
posterior pituitary gland to release oxytocin into the
bloodstream.
48
Oxytocin causes the myoepithelial cells
surrounding the alveoli to contract, forcing milk into the
ducts. This results in increased intraductal pressure,
49
duct dilation
40,50
(measured by ultrasound), and conse-
quently increased milk flow rate
50
(measured by contin-
uous weigh balance during breast expression). Multiple
milk ejections almost always occur during breastfeed-
ing
40
(mean, 2.5; range, 0–9) and breast expression
50
(mean, 3–6 for 15-minute expression period), and alhough many women are able to sense the first milk
ejection, few are able to sense subsequent ones.
While it is well known that stress can influence milk
ejection—resulting in diminished amounts of milk re-
moved by both the infant
48
and breast pump
51
—it is
often the subtle stress which affects maternal confidence
and subsequently milk ejection that is overlooked. There-
fore, it is important to provide positive support to the
mother during both breastfeeding and pumping. Another
factor that may influence milk ejection and milk removal
is the ductal anatomy of the breast. In a study of mothers
expressing with an electric breast pump, ultrasound was
used to image duct dilation in the breast that was not
pumped. It was found that mothers with larger ducts
expressed more milk during milk ejection and had longer
milk ejections than mothers with smaller ducts.
50
There-
fore, the rate of milk removal for a mother may be
influenced in part by her ductal anatomy

PREGNANCY AND BREAST PART 2

mothers with very low milk supply, breast hypoplasia
(too little glandular tissue), or hyperplasia (overgrowth of
glandular tissue). With rising rates of obesity, there is
some concern about the effect of obesity on lactation,
particularly with increasing reports that obese women are
experiencing breastfeeding difficulties (see review by
Jevitt et al. on page 606). Only a few studies have been
carried out to investigate the effect of obesity on lacta-
tion, and they have been difficult to perform because of
known confounding factors such as the mode of delivery
and parity. These studies show that pregnant women with
a high body mass index are more likely to experience
delayed lactogenesis II.
44
While the cause of delayed
lactation is not clear, hormonal influences on milk
production, increased difficulty attaining a successful
infant latch to the breast, and socio-cultural factors have
been suggested.
45
Knowledge of the normal features of the ductal system
is integral to diagnosing ductal abnormalities such as
galactoceles and blocked ducts. A palpable lump and
ultrasonic features of non-compressible ducts is indica-
tive of a blocked duct and should not be considered
“normal” for the lactating breast. Furthermore, the ultra-
sound scan may identify the level of the blockage,
providing useful information for treatment with thera-
peutic ultrasound.
Mothers of premature and sick infants rely on breast
pumps to initiate and maintain lactation. Clinically, it has
been observed that larger shield sizes may optimize milk
removal for some mothers. It is therefore feasible that
compression of superficial ducts within the breast by the
shield may indeed compromise milk flow. Further re-
search is required to determine the effect of ductal
anatomy on pumping performance in women.
Many women who have breast reduction surgery may
be able to partially breastfeed their infant, but relatively
few are able to exclusively breastfeed.
52
This is likely
because of the codistribution of glandular and fatty tissue
within both the lactating
38
and non-lactating breast,
53
making it difficult to preferentially remove fatty tissue. In
addition, milk outflow is probably disrupted, because
there are fewer numbers of ducts than previously
thought.
21,38
Furthermore, it is possible that the milk
ejection reflex may be inhibited if the nerve supply to the
nipple is disturbed.
The absence of lactiferous sinuses or milk reservoirs
leads one to reconsider the mechanism by which the
infant removes milk from the breast. Generally, it is
believed that the predominant action involved in remov-
ing milk from the breast is peristalsis or a stripping
action.
54
We have found that milk flows into the infant’s
mouth when its tongue is lowered and vacuum is applied
to the breast. This finding suggests that the vacuum
applied by the breastfeeding infant is a major component
of milk removal.
55
Indeed, it is evident that correct
positioning and attachment of the infant to the breast is
IMportant for successful breastfeeding; however, the
mechanism should be fully understood in order to diag-
nose and manage infants with sucking abnormalities.
Finally, the absence of the lactiferous sinuses further
emphasises the critical nature of milk ejection for suc-
cessful breastfeeding, because only small amounts of
milk are available before the stimulation of milk ejecTION

PREGNANCY AND BREAST

During the first half of pregnancy, extension and branch-
ing of the ductal system occurs, along with intensified
lobular–alveolar growth (mammogenesis). Growth of the
mammary gland is influenced by a number of hormones,
including oestrogen, progesterone, prolactin, growth hor-
mone, epidermal growth factor, fibroblast growth factor,
insulin-like growth factor,
28,29
and parathyroid hormone–
related protein.
30
Growth of the glandular tissue is be-
lieved to occur by invasion of the adipose tissue.
4
By
mid-pregnancy, there is some secretory development,
with colostrum present in the alveoli and milk ducts. In
the last trimester, there is a further increase in lobular
size.
While these changes typically lead to a marked in-
crease in breast size during pregnancy, the proportion of
growth varies greatly between women, ranging from
little or no increase to a considerable increase in sizE While the major increase in breast size is usually com-
pleted by week 22 of pregnancy, significant breast
growth occurs during the last trimester of pregnancy in
some women, and some women undergo significant
breast growth postpartum. At the end of pregnancy, the
volume of breast tissue had increased by 145
19 ml
(mean
standard error of the mean; n
13; range,
12–227 ml), with a further increase to 211
16 ml (n
12; range, 129–320 ml) by 1 month of lactation. The rate
of growth of the mother’s breast during pregnancy is
correlated with the increase in the concentration of
human placental lactogen in the mother’s blood, which
suggests that this hormone stimulates breast growth in
women.
31
During pregnancy, mammary blood flow approxi-
mately doubles in volume. This increased blood flow is
concomitant with both the increased metabolic activity
and temperature of the breast. This elevation in blood
flow persists during lactation and appears to decline to
prepregnancy levels about 2 weeks after weaning.
32
GROSS ANATOMY OF THE LACTATING BREAST
The breast reaches its full functional capacity at lactation,
and as a result, several internal and external changes
occur. During pregnancy, the areola darkens in colour,
and the Montgomery glands, which are a combination of
sebaceous glands and mammary milk glands, increase in
size. The secretions of these glands, which number
between 1 and 15,
33
are thought to provide maternal
protection from both the mechanical stress of sucking
and pathogenic invasion. In addition, it is also suspected
the secretion may act as a means of communication with
the infant via odor. In this connection, a recent study
demonstrated that increased numbers of Montgomery
glands is associated with increased infant weight gain in
the first 3 days after birth, infant breastfeeding behaviour
(increased latching speed and sucking activity), and
decreased time to onset of lactation in primiparous
mothers,
33
suggesting that there is indeed a functional
role of the Montgomery glands during lactation.
The standard descriptions of the human breast are
based on Cooper’s
16
magnificent cadaver dissections of
the breasts of women who were lactating at the time of
death. Although imaging modalities have become more
sophisticated, research has focused extensively on abnor-
malities of the non-lactating breast. Mammography of
the lactating breast is limited because of the increase in
glandular tissue and the secretion of breast milk, which
causes an increase in radiodensity, making images of the
breast difficult to interpret.
34
Galactography (the injection of radio-opaque contrast
media into the duct orifice at the nipple and subsequent
radiography) has illustrated only a portion of the ductal
system, and few studies have examined lactating women.
Of those that have looked at lactating breasts, some have described the milk ducts as being significantly larger
compared to those of the non-lactating breast. In contrast,
Cardenosa and Eklund
35
have reported that the ducts do
not enlarge during lactation.
To date, both computed tomography and magnetic
resonance imaging have had little to offer in elucidating
mammary anatomy. However, in two recent studies that
used magnetic resonance imaging to image the breast,
one study was able to identify some central ducts in the
breasts of lactating women,
36
and another attempted to
quantify fatty and glandular tissue volumes in the breasts
of non-lactating women.
37
These findings suggest that
this modality may offer some new insights into the
anatomy of the breast in future.
Our laboratory has recently reinvestigated the anatomy
of the lactating breast using high-resolution ultrasound.
38
Ultrasound is non-invasive and allows the structures of
the breast to be examined without distortion. Compared
with the quoted 15 to 25 ducts of conventional texts,
4,5
fewer ducts were imaged with ultrasound (mean, 9;
range, 4–8), which concurs with both Love and Bar-
sky’s
21
observations of lactating women expressing milk
with a breast pump (mean, 5; range, 1–17) and Going and
Moffatt’s
39
dissection of a nipple (4 patent ducts) from a
woman who was lactating. Interestingly, these are in
agreement with Cooper,
16
who found 7 to 12 patent ducts
in cadaver dissections of breast from a woman who was
lactating before death, although he could cannulate up to
22 ducts.
Ultrasound imaging has also elucidated other charac-
teristics of the milk ducts, in that they are small (mean, 2
mm), superficial, and easily compressed. In addition,
they do not display the typical sac like appearance of the
“lactiferous sinus” originally thought to exist (Figure 3).
Instead, branches drain glandular tissue located directly
beneath the nipple and often merge into the main
collecting duct very close to the nipple
38
(Figure 3).
Furthermore, the milk ducts increase in diameter at milk
ejection,
40
leading to the conclusion that it is likely that
the main function of the ducts is the transport rather than
storage of milk. In addition, the actual course of the ducts
from the nipple into the breast is erratic, and they are
intertwined much like the roots of a tree
38
(Figure 1),
making them difficult to separate surgically.
5
It is widely believed that the lactating breast is
predominantly composed of glandular tissue during lac-
tation. Using a semi-quantitative ultrasound measure-
ment of the glandular and adipose tissues in the breast,
we have found there to be approximately twice as much
glandular tissue as adipose tissue in the lactating breast.
However, there is great variability, and in some women,
up to half of the breast is comprised of adipose tissue. In
addition, the amount of fat situated between the glandular
tissues is highly variable. At this stage, no relationship
between the amount of glandular tissue in the breast

BLOOD ,NERVE AND LYMPH OF BREAST

the blood supply of breast is mainly by the internal Mammary artery (60%) and the lateral mammary branch
of the lateral thoracic artery (30%).
25
Smaller sources of
arterial blood include the posterior intercostal arteries
and the pectoral branch of the thoracoacromial artery.
5
There is wide variation in the proportion of blood
supplied by each artery between women,
26
and little
evidence of symmetry between breasts. Moreover, the
course of the arteries does not appear to be associated
with the ductal system of the breast.
4
Venous Drainage
The venous drainage of the breast is divided into the deep
and superficial systems which are joined by short con-
necting veins. Both systems drain into the internal
thoracic, axillary, and cephalic veins. The deep veins are
assumed to follow the corresponding mammary arteries,
while the superficial plexus consists of subareolar veins
that arise radially from the nipple and drain into the
periareolar vein, which circles the nipple and connects
the superficial and deep plexus. Symmetry of the super-
ficial venous plexus is not apparent.
25
Innervation
Cooper
16
showed that the 2nd to 6th intercostal nerves
supply the breast. The distribution and course of these
nerves are complex and variable. The anterior nerves
take a superficial course in the subcutaneous tissues,
while the lateral nerves travel a deep course through the
breast. The nipple and areola are supplied by the anterior
and lateral cutaneous branches of the 3rd to 5th intercostal nerves

ANATOMY OF NON-LACTATING BREAST

GROSS ANATOMY OF THE NON-LACTATING BREAST
For the past 160 years, the descriptions of the anatomy of
the breast have changed little since Sir Astley Cooper’s
16
meticulous dissections of breasts of women who were
lactating when they died (Figure 1).
The breast is composed of glandular (secretory) and
adipose (fatty) tissue, and is supported by a loose
framework of fibrous connective tissue called Cooper’s
ligaments. Traditional descriptions of breast anatomy
describe the glandular tissue as consisting of 15 to 20
lobes that are comprised of lobules containing between
10 and 100 alveoli that are approximately 0.12 mm in
diameter
17
(Figure 2). The size of each lobe is extremely
variable, and some lobes may differ by 20-to 30-folD.
Although it is generally thought that each lobe is a single
entity, a recent study that created three-dimensional
reconstructions of the entire ductal system (16 lobes) of
a mastectomized breast of a 69-year-old female was able
to demonstrate two connections between lobes.
19
It is
generally believed that 15 to 25 ducts drain the alveoli
and merge into larger ducts that eventually converge into
one main milk duct which dilates slightly to form the
lactiferous sinus before narrowing as it passes through
the nipple and opens onto the nipple surface (Figure 2).
Recent histologic sections of mastectomy nipples have
shown more than 17 ducts on average
18,20
; however, it is
not known whether these are all patent, and others
suggest the average number of ducts is lower (5–9).
21
The diameters of the main ducts in the non-lactating
breast as measured by ultrasound are between 1.2 mm
and 2.5 mm in diameter. Dilated ducts in the non-
lactating breast may be caused by conditions such as
polycystic ovarian disease
22
or ductal ectasia. The nipple
pores are 0.4 mm to 0.7 mm in diameter and are
surrounded by circular muscle fibres.
4,5
The heterogeneous distribution of glandular and adi-
pose tissue in the breast has hindered measurement of
these tissues. However, the ratio of glandular to adipose
tissue estimated by mammography is 1:1 on average, and
it is well documented that the proportion of glandular
tissue declines with both advancing age
23
and increasing breast size

PUBERTY AND BREAST DEVELOPEMENT

Puberty
At puberty, the increase in breast size is mainly caused
by the increased deposition of adipose tissue within the
gland. However, progressive elongation and branching of
the ducts creates a more extensive ductal network.
10
The
major site of growth is the bud-like structures at the end
of the ducts, and these form the terminal duct lobular
units or acini.
11
Although knowledge of the hormonal
regulation of mammary growth during puberty is not
extensive, these maturational changes are associated with
increased plasma concentrations of oestrogen, prolactin,
luteinizing hormone, follicle stimulating hormone, and
growth hormone.
12,13
Menstrual Cycle Changes
During the follicular phase of the menstrual cycle, the
lobules are small, with few alveoli, and there is low
mitotic activity. During the luteal phase, the lobules and
alveoli develop with open lumens and mitotic activity is
at its greatest.
14
From day 27 to menstruation, these
changes regress. However, the degeneration of the epi-
thelial growth is not complete,
15
and some of the follic-
ular growth remains until the next cycle. With increasing
years, there is a relative decrease in mitotic activity until
about 35 years of age, when breast development plateaus

NEONATAL AND PRE PUBERTAL DEVELOPEMENT OF BREAST

The ducts in the newborn breast are rudimentary and
have small, club-like ends that regress soon after birth.
Before puberty, the growth of the breast is isometric.
Allometric growth of both the stroma and epithelium
begins with the onset of puberty (8–12 years of age).
Although the impact of obesity on breast development at
this stage is unknown, it is of interest that ruminants fed
a diet that is higher than their energy requirements have
impaired mammary development and subsequent im-
paired lactation performance

FETAL DEVELOPEMENT OF BREAST

The human breast develops from a thickened ectodermal
ridge (milk line) situated longitudinally along the ante-
rior body wall from the groin to the axilla at about 6
weeks’ gestation. Regression of the ridge occurs except
for the pectoral region (2nd–6th rib), which forms the
mammary gland. Supernumerary glands may develop
anywhere along the ectodermal ridges, and in 2% to 6%
of women, these glands either mature into mammary
glands or remain as accessory nipples.
4,5
During the 7th and 8th weeks of gestation, the mam-
mary parenchyma invades the stroma, which appears as a
raised portion called the mammary disc. Between the
10th and 12th weeks, epithelial buds form; parenchymal
branching occurs during the 13th through 20th weeks.
Between the 12th and 16th weeks of gestation, the
smooth musculature of the areola and nipple are formed,
and at approximately 20 weeks’ gestation, between 15
and 25
6
solid cords form in the subcutaneous tissue.
Branching continues, and canalization of the cords oc-
curs, forming the primary milk ducts by 32 weeks’
gestation.
6
At 32 weeks’ gestation the ducts open onto the
area, which develops into the nipple.
7
The adipose tissue of
the mammary gland develops from connective tissue that
has lost its capacity to form fibres, and it is considered
necessary to further growth of the parenchyma.
4
Shortly after birth, colostrum can be expressed from
the infant’s mammary glands. This is attributed to the
pro-lactation hormones present in the fetal circulation at
birth. Regression of the mammary gland usually occurs
by 4 weeks postpartum and coincides with a decrease in
the secretion of prolactin from the anterior pituitary
gland of the infant.

INTRODUCTION AND DEVELOPEMENT OF BREAST

The human breast reaches its full functional capacity
during lactation with the production of breast milk. In
order to diagnose and treat breastfeeding problems and
pathologies that arise during lactation, it is essential to
have an extensive understanding of the normal anatomy
and physiology of the breast. This review details the
development of the breast and the most recent findings in
breast anatomy. The effect breast anatomy has upon
clinical practice as well as the importance of milk
ejection is reviewed.
DEVELOPMENT OF THE BREAST
While it is undisputed that breast milk provides the
optimal nutrition for the developing infant, breast milk
also contains unique protective factors for the mother.
1
It
has been hypothesized that the mammary gland first
evolved from the innate immune system as an inflamma-
tory response to provide protection to the young, and that
nutritional factors developed later.
2,3
To date, nutrition
has assumed a position of dominance over the protective
factors in considerations of the physiology of human
lactation.
The human breast is a dynamic organ that does not go
through all developmental stages unless a woman expe-
riences pregnancy and childbirth. The course of breast
development can be described in distinct phases begin-
ning with the fetal phase and progressing through the
neonatal/prepubertal and postpubertal phases. Develop-
ment of the breast can then proceed through a number of
lactation cycles (pregnancy, lactogenesis I, lactogenesis
II, and involution