Topics to cover

Dr. BALAJI GANJI Dr. MONICA ATUKULA

Embryology Pathology
Triple assessment
Anatomy Staging
Physiology
Etiopathogenesis of Ca breast
Risk factors for Ca breast
 BREAST
CARCINOMA
Dr. BALAJI GANJI
1st year POST GRADUATE
MS GENERAL SURGERY
EMBRYOLOGY
• Mammary glands are modified sweat glands

• During week 6 ,
The mammary glands (breasts) are derived from 2 thickened
strips of epidermal ectoderm
(the primitive mammary ridges or milk lines).

• The ridges extend from the axillae to the inguinal regions, but
rapidly regress except in the thorax.
• THE MAMMARY BUDS that persist in the thoracic region
penetrate the underlying mesenchyme by day 49and give
rise to several secondary buds (15 to 20 secondary buds)
which develop into lactiferous ducts and their branches.

• These are canalized by the end of the prenatal life

• The lactiferous ducts form the small ducts and alveoli

• Only the main ducts are found at birth, and the gland
remains undeveloped until puberty

• The fibrous connective tissue and fat of the mammary

gland develop from the surrounding mesenchyme
• DURING THE LATE FETAL PERIOD, the epidermis,
where the gland originated, becomes depressed
to form a shallow mammary pit (epithelial pit)
on which the ducts open.
• The lactiferous ducts at first open onto this
epithelial pit which is formed by the original
mammary line
• THE NIPPLE itself forms during the perinatal period
due to proliferation of the mesenchyme under the
areola (circular area of skin around the nipple) in the
area of the mammary pit.

• The nipple is often depressed and poorly formed

during infancy.
• THE MAMMARY GLANDS of both newborn males and females are often enlarged
and may secrete "witches' milk" or colostrum, as a result of maternal hormones
passing into the fetal circulation by way of the placenta.
• AT PUBERTY, the female mammary glands enlarge
rapidly as a result of the development of fat and
connective tissue.
• The duct system also grows, stimulated by the estrogen
and progesterone of the ovary.
• The glandular tissue remains completely undeveloped
until pregnancy when the intra lobular ducts rapidly
develop, form buds, and become alveoli
• The male glands undergo little postnatal development
Malformations of the mammary gland

1. Amastia ( absence of the gland )

2. Athelia ( absence of nipple )
3. Symmastia ( webbing between breasts)

May occur bilaterally or unilaterally,

due to failure of development or complete
disappearance of the mammary ridge(s) (or)
due to failure of the mammary bud to form
SUPERNUMERARY BREASTS AND NIPPLES

POLYMASTIA
POLYTHELIA
• They generally are found below the normal breast,
but less commonly are seen in the axilla or
abdominal area, developing along the mammary
ridges
• Polythelia is uncommon, also may be seen in males.
• In most cases, a single extra nipple or breast is seen,
but in 30% of cases, 2 extra nipples or breasts are
found
• Accessory breasts may have normal tissue and even
function during lactation
• Poland’s syndrome consists of
hypoplasia or complete absence of the breast, and costal cartilage
rib defects,
hypoplasia of the subcutaneous tissues of the chest wall
brachysyndactyly.
INVERTED NIPPLES:

• Due to a failure of the underlying mesenchyme

to proliferate and push the nipple out

• Also may be caused by retraction of the nipple

as a result of the presence of a fast-growing
tumor in the gland.
SIZE AND SHAPE
• Breast shape and size depend on
genetic, age,
racial, parity,
dietary factors, menopausal status.

• Breasts may be hemispherical,

conical,
variably pendulous,
piriform or
thin and flattened.
• Ectoderm penetrates underlying mesenchyme by day 49

• Nipple formation begins at day 56,

• Primitive ducts (mammary sprouts) develop at 84 days, and

• Canalization occurs at about the 150th day.

Anatomy
EXTENT
• In the adult female, the base of the breast,

vertically from the 2nd or 3rd rib To 6th rib,

transversely Medially from the sternal edge
Laterally to the mid-axillary line.

• The superolateral quadrant is prolonged towards axilla

along the inferolateral edge of pectoralis major.

• At 3rd rib level it pierces the deep fascia and extends

upto the apex of the axilla (the axillary tail of Spence).
• The trunk superficial fascial system splits to enclose
the breast to form the anterior and posterior
lamellae.

• Posterior extensions of the superficial fascial system

connect the breast to the pectoralis fascia,
part of the deep fascial system.

• The inframammary crease is a zone of adherence of

the superficial fascial system to the underlying
chest wall at the inferior crescent of the breast.
• The breast lies on the deep pectoral fascia,
which inturn overlies pectoralis major and serratus anterior
superiorly,
external oblique and its aponeurosis inferiorly,

• Between the breast and the deep fascia, the loose

connective tissue in the ‘sub mammary space’ or
‘retromammary bursa’ allows the breast some degree
of movement on the deep pectoral fascia.

• Advanced mammary carcinoma may cause tethering or

fixation of the breast to the underlying musculature.

• Occasionally, small projections of glandular tissue may

pass through the deep fascia into the underlying muscle in
normal subjects.
NIPPLE AND AREOLA
SHAPE
• The nipple projects from the center of the breast anteriorly .
• It may be cylindrical and
rounded,
hemispherical or
flattened,
depending on the effects of
developmental factors ,
mood of the person
hormonal factors
external temperature
on the erectile properties of the subareolar muscle.
LEVEL
• The level of the nipple varies widely.
• In the male, the nipple is usually sited in the fourth intercostal space in the
midclavicular line.
COLOUR
• The skin of the nipple and areola is rich in melanocytes and is therefore
typically darker. further darkening occurs during the second month of pregnancy.
• In the nulliparous, the nipple is
pink,
light brown or
darker,
depending on the general melanization of the body.
• The skin covering the nipple and the surrounding areola has
a convoluted surface.

• It contains numerous sweat and sebaceous glands that open

directly on to the skin surface.

• The oily secretion of sebaceous glands acts as a protective

lubricant and facilitates latching of the neonate during
lactation.
• The glands are often visible in parous women,
arranged circumferentially as small elevations,
(Montgomery’s tubercles), around the areola close
to the margin.

• The sebaceous glands of the areola are not usually

associated with hair follicles.
Nipple erection
• Due to Smooth muscle bundle fibers contraction
which lie circumferentially in the dense connective

tissue and longitudinally along the major ducts,

upward into the nipple,

These are responsible for the nipple erection to

sensory stimuli.
• The dermal papilla
at the tip of the nipple
contains numerous sensory nerve endings and
Meissner’ corpuscles.

• This rich sensory innervation

is of functional importance because the sucking of
the infant initiates a chain of neurohumoral events
that results in milk letdown.
SOFT TISSUE
• The breasts are composed of lobes that contain a
network of glandular tissue.
• The terminal duct lobular unit is the functional
milk secretory component of the breast;
• Pathologically,it gives rise to primary malignant
lesions within the breast.
• Although the lobes are usually described as
discrete territories, they inter wine in three
dimensions and merge at their edges, they
cannot be distinguished during surgery.
• Intralobular connective tissue has a loose texture that
allows the rapid expansion of secretory tissue during
pregnancy.

• Fibrous strands or sheets consisting of condensations

of connective tissue extend between the layer of deep
fascia that covers the muscles of the anterior chest wall
and the dermis (Astley Cooper ligaments).
• These suspensory ligaments are often well developed in the
upper part of the breast and support the breast tissue,
helping to maintain its non-ptotic form.

• Elsewhere in the normal breast, fibrous tissue surrounds the

glandular components and extends to the skin and nipple,
assisting the mechanical coherence of the gland.

• The interlobar stroma contains variable amounts of adipose

tissue.

• This is responsible for much of the increase in breast size at

puberty.
MICRO STRUCTURE
DUCTS
• The ducts are lined by columnar epithelium.
• In the larger ducts, this is two cells thick but,
in the smaller ones, only a single layer of columnar or cuboidal
cells is present.
• The bases of these cells are in close contact with numerous
myoepithelial cells of ectodermal origin, similar to those of
certain other glandular epithelia.
• Myoepithelial cells are so numerous that they form a distinct
layer surrounding the ducts and presumptive alveoli, and give
the epithelium a bilayered appearance.
• Lactiferous ducts draining each lobe of the breast pass through the nipple and
open on to its tip as 15–20 orifices.
• Near its orifice, each of these ducts is slightly expanded as a lactiferous sinus,
in the lactating breast, is further dilated by the presence of milk.
LOBE
• Each lactiferous duct is connected to a system
of ducts and lobules,
surrounded by connective tissue stroma,
collectively forming a lobe of the breast.
LOBULES
• Consists of a cluster of blind-ended, branched ductules,
which are the sites of milk secretion in the lactating
breast.
• Lobules consist of the portions of the glands that
have secretory potential.

• Their structure varies according to hormonal status.

• In the mature resting breast, each lobule consists of a

cluster of blind-ended, branched ductules, whose
termini lack mature terminal alveoli (acini), which are
the sites of milk secretion in the lactating breast.
• The stratified cuboidal lining is replaced by keratinized
stratified squamous epithelium, continuous with the
epidermis, close to the openings of the lactiferous
ducts on the nipple.

• Shed squames may sometimes block the duct apertures in

the nonpregnant breast.
NIPPLE
• Internally, the nipple is composed mostly of
collagenous dense connective tissue and contains
numerous elastic fibres that wrinkle the overlying
skin.
• Deep to the nipple and areola, bundles of smooth
muscle cells are arranged radially and
circumferentially within the connective tissue.
• Their contraction, induced by cold or tactile stimuli
(e.g. in suckling), causes erection of the nipple and
wrinkling of the surrounding areola.
BLOOD SUPPLY AND
LYMPHATICS
Arterial supply
The breast receives its principal blood supply from:
(a) Perforating branches of the internal mammary (thoracic) artery;
(b) Lateral branches of the posterior intercostal arteries; and
(c) Branches from the axillary artery,
including the 1. highest thoracic (superior thoracic artery),
2. thoracoacromial artery
lateral thoracic, and
pectoral branches
• branches of the internal mammary artery i.e The second, third, and fourth
anterior intercostal perforators and arborize in the breast as the medial
mammary arteries.
• The lateral thoracic artery gives off branches arborise in the breast as
lateral mammary arteries .
 Arch of Aorta
Thoracic Aorta

Brachiocephalic artery Posterial intercostal arteries

Rt common carotid artery
Lateral branches
Rt subclavian artery Axillary artery

Vertebral artery.
Internal (mammary) thoracic artery. 2nd part 3rd part
1 part
st
Thyrocervical trunk. Thoraco acromian artery Ant circumflex humeral
Superior thoracic artery
Lateral thoaracic artery Post circumflexhumeral
Costocervical trunk. Sub scapular
Dorsal scapular artery. Circumflex scapular
Thoraco dorsal

Mediastinal branches
Thymic branches
Pericardiacophrenic artery - travels with the phrenic nerve
Sternal branches
Perforating branches
Twelve anterior intercostal branches
Venous drainage
The veins of the breast and chest wall follow the
course of the arteries, with venous drainage being
toward the axilla.
The three principal groups of veins are:
(a) perforating branches of the internal thoracic vein,
(b) perforating branches of the posterior intercostal veins, and
(c) tributaries of the axillary vein.
generally parallel the course of blood vessels.
Batson’s vertebral venous plexus,
These invests the vertebrae and extends from
the base of the skull to the sacrum,
may provide a route for breast cancer
metastases to the
vertebrae,
skull,
pelvic bones, and
central nervous system.
Lymphatic
drainage
The boundaries for lymph drainage of the axilla are not well
demarcated, and there is considerable variation in the position of
the axillary lymph nodes.

The six axillary lymph node groups recognized by surgeons

(a) The axillary vein group (lateral),
(b) The external mammary group (anterior or pectoral group)
(c) The scapular group (posterior or subscapular),
(d) The central group
(e) The sub clavicular group (apical),
(f) The interpectoral group
The lymph node groups are assigned levels according to their
anatomic relationship
to the pectoralis minor muscle.
Level 1 lateral to or below the lower border of the pectoralis
minor muscle are
external mammary(ant) and
scapular groups (post)
Level 2 superficial or deep to the pectoralis minor muscle
the central and
interpectoral groups(rotters).
Level 3 medial to or above the upper border of the pectoralis
minor muscle are
sub clavicular group(apical).
• The plexus of lymph vessels in the breast arises in the
interlobular connective tissue and in the walls of the
lactiferous ducts and communicates with the sub
areolar plexus of lymph vessels.
• Efferent lymph vessels from the breast pass around
the lateral edge of the pectoralis major muscle and
pierce the clavipectoral fascia, ending in the external
mammary (anterior, pectoral) group of lymph nodes.
• Some lymph vessels may travel directly to the
subscapular (posterior, scapular) group of lymph
nodes.
• From the upper part of the breast, a few lymph
vessels pass directly to the subclavicular (apical)
group of lymph nodes.
PHYSIOLOGY OF THE BREAST
• Breast development and function are initiated by a variety of
hormonal stimuli, including
estrogen,
progesterone,
prolactin,
oxytocin,
thyroid hormone,
cortisol, and
growth hormone.
• Estrogen, progesterone, and prolactin especially have profound
trophic effects that are essential to normal breast development
and function.
• Estrogen initiates ductal development,
Progesterone is responsible for differentiation of epithelium and for lobular development.
Prolactin is the primary hormonal stimulus for lactogenesis in
late pregnancy and
postpartum period.
• The release of LH and FSH from the basophilic cells of the anterior pituitary
is regulated by the secretion of gonadotropin-releasing hormone
(GnRH) from the hypothalamus.
• The gonadotropins
luteinizing hormone (LH) and
follicle-stimulating hormone (FSH)
regulate the release of estrogen and progesterone from the ovaries.
• Positive and negative feedback effects of circulating estrogen and progesterone
regulate the secretion of LH, FSH, and GnRH.
• These hormones are responsible for the
development,
function, and
maintenance of breast tissues.
• In the female neonate, circulating estrogen and progesterone levels decrease
after birth and remain low throughout childhood because of the sensitivity of
the hypothalamic-pituitary axis to negative feedback from these
hormones.
• With the onset of puberty, there is a decrease in the sensitivity of the
hypothalamic-pituitary axis to negative feedback and an increase in its sensitivity
to positive feedback from estrogen.
• These physiologic events initiate an increase in GnRH, FSH, and LH secretion and
ultimately an increase in estrogen and progesterone secretion by the ovaries, leading to
establishment of the menstrual cycle.
• At the beginning of the menstrual cycle, there is an increase in the size and
density of the breasts, which is followed by engorgement of the breast tissues
and epithelial proliferation.
• With the onset of menstruation, the breast engorgement subsides and epithelial
proliferation decreases.
Pregnancy, Lactation, and Senescence

• A dramatic increase in circulating

ovarian and placental estrogens and progestins
is evident during pregnancy,
which initiates striking alterations in the substance of the breast
• The breast enlarges as the ductal and lobular epithelium proliferates, the areolar
skin darkens, and the accessory areolar glands (Montgomery’s glands) become
prominent.
• In the first and second trimesters, the minor ducts branch and develop.
• During the third trimester, fat droplets accumulate in the alveolar epithelium, and
colostrum fills the alveolar and ductal spaces.
• In late pregnancy, prolactin stimulates the synthesis of milk fats and proteins.
• After delivery of the placenta,
circulating progesterone and
estrogen
levels decrease, permitting full expression of the lactogenic action of prolactin.
• Milk production and release are controlled by neural reflex arcs that originate in
nerve endings of the nipple-areola complex.
• Maintenance of lactation requires regular stimulation of these neural reflexes,
which results in prolactin secretion and milk letdown.
• Oxytocin release results from the auditory, visual, and olfactory stimuli associated
with nursing.
• Oxytocin initiates contraction of the myoepithelial cells, which results in
compression of alveoli and expulsion of milk into the lactiferous sinuses.
• After weaning of the infant, prolactin and oxytocin release decreases. Dormant
milk causes increased pressure within the ducts and alveoli, which results in
atrophy of the epithelium.
• With menopause,
there is a decrease in the secretion of estrogen and progesterone by the ovaries
and involution of the ducts and alveoli of the breast.
• The surrounding fibrous connective tissue increases in density,
and breast tissues are replaced by adipose tissues.
Risk Factors for Ca breast
Sex
Female sex - 99%
the major risk factors are related to hereditary factors,
lifetime exposure to estrogen and,
to a lesser extent, environmental or lifestyle factors.
Age
Breast cancer risk rises throughout a woman’s lifetime,
peaking at 70 to 80 years and then
Declinine slightly thereafter
Age at menarche.

• Menarche at ages younger than 11 years increases risk by 20%

compared to menarche at ages greater than 14.
• Late menopause also increases risk.
Age at first live birth

A full-term pregnancy before the age of 20 halves the risk compared to

Nulliparous women or women who are older than the age of 35 at the
time of their first birth
Germline mutations

Approximately 5% to 10% of breast cancers occur in persons with

germline mutations in tumor suppressor genes.

For these individuals, the lifetime risk of breast cancer can be

more than 90%
First-degree relatives

About 15% to 20% of women with breast cancer have an affected firstdegree
relative (mother, sister, or daughter), but do not carry an identified breast cancer
gene mutation.

This increased risk is probably due to the interaction of low risk susceptibility genes
and
shared environmental factors.

It is important to note that, risk is not increased

if the only affected relative is a postmenopausal mother with cancer.
Race/ethnicity
Estrogen exposure

• Menopausal hormone therapy increases the risk of breast cancer,

particularly when estrogen and a progestin are given together for a period
of years.
• Most excess cancers are small ER-positive carcinomas.
• In contrast, oral contraceptives do not appear to increase the risk of breast
cancer.
• Reducing endogenous estrogens by oophorectomy decreases the risk of
developing breast cancer by up to 75%.
Obesity

Obese women under the age of 40 have a decreased risk as a result of anovulatory
cycles and lower progesterone levels.

In contrast, postmenopausal obese women are a increased risk, which is attributed

to the synthesis of estrogens in fat depots
Diet

Large studies have failed to find strong correlations between breast cancer risk and
dietary intake of any specific type of food.

Moderate or heavy alcohol consumption increases risk

Breastfeeding

• The longer women breastfeed, the greater the reduction in risk.

• Lactation suppresses ovulation and may trigger terminal differentiation of
luminal cells.
• The lower incidence of breast cancer in developing countries can largely be
explained by the more frequent and longer nursing of infants.
Breast density

• Women with very dense breasts on mammography have a 4 to 6 fold

higher risk of both ER-positive and ER-negative breast cancer compared
to women with the lowest density.

• Persistently high breast density in older women may stem from a failure of
normal breast involution
Radiation exposure

• Radiation to the chest,

whether for cancer therapy,
due to atomic bomb exposure, or
nuclear accidents,
results in a higher rate of breast cancer.

• The risk is greatest with exposure at young ages and with high radiation doses.

• Older women undergoing radiation do not incur this risk.

Carcinoma of the contralateral breast or endometrium

• Approximately 1% of women with breast cancer develop a second contralateral

breast carcinoma per year.
Benign breast disease

A prior breast biopsy revealing

atypical hyperplasia or proliferative changes
increases the risk of invasive carcinoma.
Exercise

• There is a probable small protective effect for women who are

physically active

Environmental toxins

• Organochlorine pesticides, have estrogenic effects on humans.

• Definitive associations have yet to be made.
Etiology and Pathogenesis
• Breast cancers are clonal proliferations that arise from
cells with multiple genetic aberrations,
acquisition of which is influenced by
hormonal exposures and
inherited susceptibility genes.

• Breast cancers may be

1)hereditary (germline mutations in tumor suppressor genes)
2) sporadic

• The identification of breast cancer susceptibility genes has provided important

insights into the pathogenesis of both familial and sporadic forms of breast cancer
Familial Breast Cancer
• Approximately 12% of breast cancers occur due to inheritance of an identifiable
susceptibility gene or genes.
• A single sporadic mutation in the remaining normal allele
is all that is required
to completely lose tumor suppressor function.
• The major known susceptibility genes for familial breast cancer
BRCA1, BRCA2, All are l tumor suppressor genes
role - DNA repair and
TP53, and CHEK2 maintenance of genomic integrity
• It is likely that complete loss-of-function of these proteins creates a “mutator”
phenotype, an increased propensity to accumulate genetic damage that speeds
cancer development
• Mutation in BRCA1 also markedly increase the risk of developing ovarian
carcinoma,
• Mutations in BRCA2 confers a smaller risk for ovarian carcinoma(10% to 20%) but
is associated more frequently with male breast cancer.
• BRCA1 and BRCA2 carriers are also at higher risk for other epithelial cancers, such
as prostatic and pancreatic carcinomas.
• Mutations in genes
BRCA1 90 %
BRCA2

TP53 (Li-Fraumeni syndrome) 8%

CHEK2

PTEN (Cowden syndrome),

<1%
STK11 (Peutz-Jeghers syndrome),
ATM (ataxia telangiectasia).
• Most of these genes play complex and interrelated roles in maintaining genomic integrity.

• After a cell sustains DNA damage, it must undergo cell cycle arrest and
Either repair its DNA or die by apoptosis.

• ATM senses DNA damage and with p53 and CHEK2 induces cell cycle arrest.

• BRCA1, BRCA2, and CHEK2 all have important functions in repair of double
stranded DNA breaks.
• BRCA1 and BRCA2 are part of a large complex of proteins that are required to
repair double stranded DNA breaks through a process called homologous
recombination, in which a normal sister chromatid is used as a template for
repairing the broken stretch of DNA.

• If any of these functions are impaired, the cells with permanent DNA damage will
survive is increased and the mutation will be propagated
BRCA 1 BRCA 2
• Present on chr 17q21 • Present on chr 13q 12-13

• Mutations also increases risk for ovarian • Mutations also increases risk for ovarian cancer
cancers markedly (20-40 % of carriers ) (10-20 % of carriers )

• associated breast cancers are commonly • BRCA2-associated breast carcinomas also tend
poorly differentiated, have “medullary to be relatively poorly differentiated
features” a syncytial growth pattern with
pushing margins and a lymphocytic response

• Are biologically very similar to • are more often ER-positive than BRCA1 cancers
ER-negative/HER2-negative breast cancers
• BRCA1 and BRCA2, is more highly associated with breast cancer than other Cancers

• BRCA1 and BRCA2 are expressed ubiquitously,

so the link to breast cancer is not obviously explained by tissue-specific patterns
of gene expression

• An alternative possibility is that breast (and ovarian) epithelial cells may be

Particularly prone to suffer the type of DNA damage that BRCA1 and BRCA2 are
required to repair.

• BRCA1 also interacts with protein complexes that regulate chromatin structure, and
it remains possible that its tumor suppressive role involves functions that are
independent of DNA repair.
Identification of carriers is important, Since
increased surveillance,
prophylactic mastectomy, and
salpingo-oophorectomy
can reduce cancer-related morbidity and mortality
Sporadic Breast Cancer

The major risk factors for sporadic breast cancer are related to hormone exposure:
gender,
age at menarche
menopause,
reproductive history,
breastfeeding,
exogenous estrogens.
Environmental risk factors, proven or suspected, include
radiation exposure and
exposure to chemicals with estrogen-like effects.
• Estrogen clearly functions as a promoter of breast cancers ,
Hormonal exposure stimulates breast growth
during puberty,
menstrual cycles, and
pregnancy,
thereby increasing the number of cells that can potentially give rise to a cancer.

• The proliferation of breast epithelium during the menstrual cycle is also

conducive to the accumulation of DNA damage, and the temporary lull in cell
division that occurs during the latter part of the menstrual cycle may allow time
for defective DNA repair to occur and for mutations to become “fixed” in the
genome.

.
• Repeated rounds of this process during each cycle may underlie the association
between the cumulative number of menstrual cycles a woman experiences and
her risk of developing breast cancer.

• Once premalignant or malignant cells are present, hormones can stimulate their
growth as well as the growth of normal stromal cells that may aid and abet tumor
development
Molecular Mechanisms of Carcinogenesis
• The diverse histologic appearances of breast carcinomas are the outward
manifestations of the complex genetic and epigenetic changes that drive
carcinogenesis.

• Resident breast tissue stem cells have been hypothesized to be the cell of origin
for all breast cancers

• Once the process is initiated in such cells by a driver mutation,

there appear to be three major genetic pathways of carcinogenesis.
1) ER POSITIVE PATHWAYS (ER +,HER2 -)
2) ER NEGATIVE PATHWAYS(ER -,HER2 -)
3) HER2 POSITIVE PATHWAYS(HER 2 +,ER+/-)
ER-positive, HER2-negative cancers

• Dominant pathway,
• Constituting 50% to 65% of cases,
• They are often associated with
gains of chromosome 1q,
losses of chromosome 16q, and
activating mutations in PIK3CA,
• PIK3CA is a gene that encodes Phospho-Inositide 3 kinase (PI3K),
which is an important component of signaling pathways downstream of growth
factor receptors.
• These genetic lesions are often found in
flat epithelial atypia and
atypical ductal hyperplasia,
which are hypothesized to be precursor lesions for this subtype of breast cancer.

• ER-positive cancers are termed “luminal,” as these cancers most closely resemble
normal breast luminal cells in terms of their mRNA expression pattern.
• Tumors arising through this pathway include at least two major molecular
subtypes
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