Pathogenesis of Breast Cancer

Slide 1 · Pathogenesis of Breast Cancer

Molecular evolution • inherited susceptibility • tumour microenvironment

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · What this lecture explains

How initiating genomic events and cell context shape breast carcinoma phenotype.

Why low-grade and high-grade neoplasia often follow different evolutionary pathways.

How inherited susceptibility, hormones, and acquired alterations converge.

Why invasion also depends on epithelial–stromal and immune interactions.

Slide 3 · Breast cancer is an evolutionary process

Initiating driver event

Clonal expansion

Additional molecular changes

In situ neoplasia

Invasive carcinoma

A useful conceptual model—not every tumor passes through a morphologically identifiable precursor.

Slide 4 · Initiation is not independent of cell context

Initiating alteration

Epithelial context

An inherited or acquired driver can establish the first transformed clone.

Its molecular consequences constrain later evolutionary options.

The epithelial cell in which the event occurs may influence phenotype.

Different lineages and differentiation states can yield different outcomes.

Slide 5 · Two major evolutionary routes

Low-grade route

ER-positive precursor lesions

Luminal, usually lower grade

In parallel: A high-grade route leads to heterogeneous luminal B, HER2-positive, or triple-negative tumors; The routes can intersect.

Slide 6 · Why terminal duct–lobular anatomy matters

Most breast carcinomas are thought to arise in the terminal duct–lobular unit.

“Ductal” and “lobular” describe growth and cohesion patterns, not necessarily distinct cells of origin.

In situ disease remains bounded by a basement membrane; Invasion breaches that interface.

Myoepithelial and stromal interactions help maintain normal compartmental architecture.

Slide 7 · Three clinical molecular categories

Luminal

ER-positive / HER2-negative

Typically hormone-dependent

HER2-positive

HER2 amplified / overexpressed

ER may be positive or negative

Triple-negative

ER-, PR-, HER2-negative

Molecularly heterogeneous

Clinical biomarker categories overlap imperfectly with intrinsic expression subtypes.

Slide 8 · Biomarker groups ≠ expression signatures

Routine biomarker grouping

Intrinsic molecular grouping

ER, PR and HER2 protein/gene status guide clinical grouping.

Provides practical information about biological dependencies.

Gene-expression profiling distinguishes luminal A, luminal B and basal-like patterns.

The two frameworks overlap, but are not perfectly interchangeable.

Slide 9 · Evolution is heterogeneous, not a single sequence

Low-grade and high-grade tumors commonly have different genomic architectures.

Tumor cell proliferation, DNA repair capacity, and selective pressures shape progression.

Atypical lesions may remain noninvasive; Progression is not inevitable.

A subset of lower-grade tumors can acquire high-grade molecular changes.

Slide 10 · Four interlocking determinants of pathogenesis

Genotype

Driver alterations

Oncogenes and suppressors

Cell state

Luminal lineage

Differentiation phenotype

Exposure

Hormonal context

Estrogen-linked growth

Environment

Stroma and immunity

Invasion and escape

Breast carcinoma phenotype is a systems-level product of these influences.

Slide 11 · Low-grade pathway: A multistep model

Columnar cell change

Flat epithelial atypia

Atypical ductal hyperplasia

Low-grade DCIS

Low-grade invasive cancer

Schematic sequence: The pathway is associated with ER-positive luminal neoplasia; Individual lesions do not inevitably progress.

Slide 12 · Columnar cell lesions: Earliest recognizable changes

Variably dilated acini are lined by columnar epithelial cells.

Microcalcifications may draw attention to these lesions on screening.

Some lesions belong to the low-grade neoplastic continuum.

Their appearance provides morphological evidence of early epithelial change.

Slide 13 · Flat epithelial atypia versus atypical hyperplasia

Flat epithelial atypia

Atypical ductal hyperplasia

Columnar cell lesion with cytologic atypia.

Does not show the architectural complexity of atypical ductal hyperplasia.

Monomorphic cells in organized patterns, often cribriform or micropapillary.

Resembles low-grade DCIS but is limited in extent.

Slide 14 · Ductal and lobular atypia are related—not identical

Atypical ductal hyperplasia

Atypical lobular hyperplasia

Cohesive, regular population with low-grade ductal-type architecture.

Morphologically related to low-grade DCIS.

Dyscohesive epithelial population within duct–lobular spaces.

Morphologically resembles classic LCIS but is less extensive.

Slide 15 · Carcinoma in situ has already acquired cancer features

Neoplastic epithelial cells remain within ducts or lobules enclosed by basement membrane.

Many molecular driver changes are shared with the associated invasive carcinoma.

The in situ designation is defined by location, not biological innocuousness.

An intact barrier is the defining distinction from invasive carcinoma.

Slide 16 · Low-grade in situ neoplasia is not one uniform entity

Low-grade DCIS

Ductal-type architecture

A common precursor of low-grade invasion

Classic LCIS

Dyscohesive luminal cells

Lobular neoplasia pathway

Atypical lesions

Partial neoplastic features

Risk and precursor significance

These lesions share ER-positive low-grade biology but should not be forced into one linear chain.

Slide 17 · Low-grade pathway: Genomic fingerprint

16q loss

Copy-number loss

Characteristic genomic event

1q gain

Copy-number gain

Characteristic genomic event

Luminal program

ER-associated transcription

Characteristic expression pattern

The recurring molecular signature supports relatedness among low-grade precursors and invasive lesions.

Slide 18 · Loss of chromosome arm 16q: A recurring clue

Loss of 16q is characteristic of the low-grade neoplasia pathway.

The alteration is detected at the genomic level rather than inferred from microscopic appearance alone.

It can occur in noninvasive lesions, consistent with early clonal evolution.

Its presence alone does not prove inevitable invasion.

Slide 19 · Gain of chromosome arm 1q: Clonal progression

Gain of 1q commonly accompanies the low-grade molecular pathway.

Copy-number change may precede the development of invasive disease.

Recurrent low-grade alterations help distinguish this route from genomically chaotic high-grade neoplasia.

Copy-number patterns are not stand-alone clinical diagnostic tests in this lecture.

Slide 20 · PIK3CA activation provides growth signaling

PIK3CA mutation

Altered PI3K signaling

Enhanced growth / survival signals

Clonal advantage

PIK3CA mutations are common in luminal A cancers; This schematic simplifies the downstream network.

Slide 21 · The luminal expression program is an identity

Luminal cancers express genes regulated by estrogen receptor signaling.

Hormone-responsive transcription is a molecular phenotype, not merely a positive stain.

ER expression links lineage differentiation to growth dependence.

Degree of proliferation helps distinguish lower- from higher-risk luminal programs.

Slide 22 · Risk lesion does not mean predestined cancer

What precursor lesions establish

What precursor lesions do not establish

A clone with recognizable neoplastic features exists.

Its genotype can overlap with later carcinoma.

That every lesion will progress to carcinoma.

That invasion requires a new universally identifiable driver mutation.

Slide 23 · High-grade pathway: The broad model

Early initiating event (often occult)

Genomic instability

High-grade DCIS

High-grade invasive cancer

Earlier high-grade precursors are incompletely defined; The model does not assert a mandatory sequence.

Slide 24 · The earliest high-grade precursor remains uncertain

High-grade DCIS is a recognized major noninvasive counterpart of high-grade invasion.

Morphologically earlier precursor lesions are much less well characterized.

Rapid progression before detection may obscure intermediate steps.

Absence of a recognized precursor is not evidence that there was no precursor.

Slide 25 · Low-grade versus high-grade evolution

Low-grade route

High-grade route

Recognizable atypical and low-grade in situ lesions.

Often ER-positive with 1q gain / 16q loss.

Generally less genomic instability.

Earlier steps frequently unrecognized.

High-grade DCIS often demonstrable.

More genomic abnormalities and proliferation-associated expression.

Slide 26 · High-grade genomic instability is foundational

High-grade tumors frequently show complex copy-number alterations and rearrangements.

Genomic instability creates new variants from which selection can act.

DNA-repair failure and disrupted cell-cycle checkpoints can amplify genomic disruption.

The degree of instability differs among molecular subtypes.

Slide 27 · TP53 dysfunction favors genomic evolution

TP53 pathway disruption

Impaired damage response

Survival of abnormal clones

Further genomic complexity

TP53 mutations occur frequently in high-grade pathways, particularly many triple-negative tumors.

Slide 28 · Reported high-grade genomic changes

13q loss

Copy-number loss

Associated with high-grade pathway

11q13 gain

Copy-number gain

Reported high-grade alteration

17q12 gain

HER2 region

Amplification in HER2-driven cancers

These are associations evolutionary model—not a universal diagnostic panel.

Slide 29 · Low-grade and high-grade routes can intersect

Largely separate but not mutually exclusive trajectories.

Some luminal cancers acquire additional abnormalities and become more proliferative.

Acquired defects in genome-stability pathways may enable grade progression.

A higher-grade phenotype need not imply a wholly independent cell of origin.

Slide 30 · High-grade biology yields multiple phenotypes

Luminal B

ER-associated, higher proliferation

May evolve from luminal lesions

HER2 positive

ERBB2 amplification

Receptor-driven signaling

Triple-negative

Often HR repair defective

ER-independent and HER2-negative

The shared feature is not one mutation, but frequently accelerated evolution and genomic complexity.

Slide 31 · Familial and sporadic cancers converge

Inherited susceptibility

Sporadic development

Constitutional variant predisposes epithelial clones.

Subsequent somatic events complete tumor evolution.

Often affects DNA repair / genomic stability.

Driver events accumulate without a recognized highly penetrant inherited syndrome.

Hormonal influences and acquired genomic changes remain important.

Can converge on similar molecular phenotypes.

Slide 32 · Family history is biologically informative

Inherited susceptibility contributes through rare high-penetrance genes and lower-penetrance variants.

A positive family history may reflect multiple interacting risk alleles.

Absence of a striking pedigree does not rule out a genetic contribution.

“Familial” is broader than BRCA-associated cancer.

Slide 33 · Penetrance is a probability, not a destiny

Penetrance is the risk that a carrier of a susceptibility variant develops cancer.

Risk depends on the variant and potentially other inherited factors.

High- and moderate-penetrance genes differ in effect magnitude.

A germline pathogenic variant is susceptibility—not itself a diagnosis of carcinoma.

Slide 34 · Inherited tumor-suppressor defects: Two hits

Germline loss-of-function allele

Normal allele remains

Somatic loss of remaining allele

Biallelic dysfunction

Clonal selection

Autosomal dominant inheritance of cancer susceptibility can coexist with recessive gene inactivation within the tumor.

Slide 35 · BRCA1 and BRCA2: Central susceptibility genes

BRCA1 and BRCA2 account for a major fraction of single-gene hereditary breast cancer.

Both proteins contribute to repair of double-strand DNA breaks by homologous recombination.

Pathogenic variants also confer susceptibility to selected cancers outside the breast.

The resulting breast cancer phenotype differs between BRCA1 and BRCA2 carriers.

Slide 36 · BRCA1-associated versus BRCA2-associated cancer

BRCA1-associated tumors

BRCA2-associated tumors

Frequently triple negative description.

May arise from defects affecting breast progenitor differentiation.

Homologous recombination repair is compromised.

A majority are ER-positive.

Luminal B-type biology can be observed.

Homologous recombination repair is compromised.

Slide 37 · Homologous recombination repairs double-strand breaks

Double-strand DNA break

Sister chromatid template

BRCA-linked repair machinery

Accurate sequence restoration

Homologous recombination is especially important for maintaining genomic integrity during cell replication.

Slide 38 · DNA-repair susceptibility is a network

BRCA1 / BRCA2

Homologous recombination

Core breast predisposition genes

PALB2 / RAD51C / RAD51D

Repair-associated proteins

Genome maintenance

ATM / CHEK2

Damage response

Checkpoint and repair context

These interconnected genes are associated with familial susceptibility in the source text.

Slide 39 · Biallelic DNA-repair loss accelerates instability

Inherited risk allele

Loss of second functional allele

Deficient homologous recombination

Unrepaired / misrepaired lesions

Tumor evolution

The defining mechanism is genome maintenance failure, not a specific histologic architecture.

Slide 40 · Synthetic lethality exploits repair dependence

Homologous-recombination-deficient tumor cells already lack a major DNA-repair pathway.

PARP inhibitors disrupt repair of additional DNA lesions.

Combined defects can create lethal genomic damage selectively in vulnerable tumors.

Normal cells with intact homologous recombination retain an alternative repair capacity.

Slide 41 · PARP inhibition: Mechanism in four stages

HR-deficient tumor

PARP inhibition

Accumulated DNA damage

Tumor cell death

Simplified mechanism underlying sensitivity to PARP inhibition; Not a comprehensive treatment selection guideline.

Slide 42 · Why BRCA loss predisposes to breast cancer is unresolved

BRCA proteins function widely throughout the body, yet cancer susceptibility is tissue biased.

Proposed explanations include lineage-specific differentiation and hormonal survival signals.

Epithelial tissues may differ in the DNA damage types they experience.

These ideas are hypotheses, not a settled single mechanism.

Slide 43 · A proposed BRCA1–progenitor link

ER-negative progenitor

BRCA1-dependent differentiation

ER-positive luminal cell

Hypothesis: Impaired differentiation following BRCA1 loss may leave a genetically unstable progenitor compartment; This causal model remains tentative.

Slide 44 · Risk architecture: Monogenic and polygenic

Single-gene high/moderate effects

Lower-penetrance combinations

Loss-of-function variants in genes regulating stability or growth.

Often recognizable through familial clustering or associated cancer syndromes.

Multiple polymorphic variants can jointly modify susceptibility.

One variant may have only a modest measurable impact on individual risk.

Slide 45 · Sporadic luminal cancer is hormone linked

The luminal ER-positive/HER2-negative pathway accounts for a large proportion of breast cancers.

Cumulative estrogen exposure is a major biologic risk factor.

Estrogen may influence both emergence and subsequent growth of mutated clones.

Hormone antagonism provides clinical evidence of estrogen dependence.

Slide 46 · Estrogen can amplify local growth signals

Estrogen–ER signaling

Growth factor production

Epithelial proliferation

Expansion of susceptible clones

TGF-α, PDGF and FGF among estrogen-associated local growth factors.

Slide 47 · Estrogen acts as a transcriptional regulator

Estrogen exposure

Nuclear ER action

Gene-expression changes

Growth / survival phenotype

Many ER-regulated genes can contribute to epithelial growth and cancer evolution.

Slide 48 · Repeated proliferation increases mutation opportunity

Menstrual cycling

Epithelial replication

DNA replication errors / damage

Clonal alterations

The proposed link is increased opportunities for mutation and fixation during repeated cycles; This is mechanistic interpretation.

Slide 49 · Reproductive and environmental context modifies risk

Earlier menarche and later menopause increase cumulative menstrual cycling.

Late first pregnancy and nulliparity are associated with increased risk.

Prolonged breastfeeding and early pregnancy are associated with lower risk.

Postmenopausal obesity, activity and alcohol are modifiable influences described in the text.

Slide 50 · A hormone-responsive clone still needs other events

Clonal ER-positive cells

Estrogen-supported proliferation

Further acquired alterations

Selected malignant clone

Most low-grade precursor lesions never develop invasive cancer; ER stimulation alone is not sufficient.

Slide 51 · Luminal A: Differentiated, hormone-regulated program

Strong expression of estrogen-regulated and luminal genes.

Often strongly ER-positive and PR-positive.

Typically lower proliferation and well-differentiated morphology.

Frequent alterations include 1q gain, 16q loss and PIK3CA activation.

Slide 52 · Luminal B: A more proliferative luminal state

Retains a luminal component but expresses more proliferation-associated genes.

Usually higher grade, with lower ER/PR expression than luminal A.

More chromosomal aberrations are often present.

Can arise after additional genetic changes in a luminal precursor population.

Slide 53 · Luminal A and B: Biological contrasts

Feature

Luminal A tendency

Luminal B tendency

Gene program

Strong ER-regulated

Proliferation enriched

Proliferation

Lower

Higher

Differentiation

Better

Less differentiated

Genomic burden

Often lower

Often greater

Slide 54 · PI3K activation links genotype to phenotype

PIK3CA alteration

PI3K signaling

AKT-linked survival signaling

Growth advantage

A conceptual molecular axis; The complete pathway contains additional receptors and feedback loops.

Slide 55 · HER2-positive carcinoma is gene-amplification driven

Amplification of the ERBB2 / HER2 region on chromosome 17q is central.

HER2 is a receptor tyrosine kinase with growth-promoting activity.

HER2-positive cancers may express ER or be ER-negative.

Gene amplification underlies the great majority of HER2 protein overexpression in the source.

Slide 56 · HER2 drives mitogenic and survival pathways

ERBB2 amplification

HER2 receptor excess

RAS and PI3K–AKT activity

Proliferation / survival

Conceptual receptor signaling chain; HER2-driven tumors often show additional genomic alterations.

Slide 57 · HER2 tumors combine signaling with instability

HER2 amplification is often accompanied by complex chromosomal rearrangements.

TP53 and PIK3CA mutations are frequently observed.

Amplified oncogenic signaling increases proliferation and opposes apoptosis.

The high-grade phenotype reflects both receptor activity and accumulated genomic change.

Slide 58 · HER2 molecular change versus its detection

Underlying mechanism

Observable clinical biomarkers

ERBB2 locus amplification increases gene copy number.

HER2 receptor overexpression drives downstream signaling.

IHC can demonstrate protein overexpression.

In situ hybridization can assess gene amplification.

These are related but technically distinct assays.

Slide 59 · Triple-negative cancer is defined by what it lacks

No detectable ER, PR or HER2 by the defining clinical biomarker criteria.

The group is heterogeneous and not one molecular disease.

Most common high-grade triple-negative cancers have an ER-independent phenotype.

A minority of special low-grade histologic tumors are also triple-negative.

Slide 60 · Triple-negative is not synonymous with basal-like

Triple-negative biomarker phenotype

Basal-like expression subtype

Defined by absence of ER, PR and HER2.

Comprises biologically distinct tumors.

Defined by a molecular expression program.

Often expresses basal / myoepithelial-associated genes.

Overlaps substantially, but incompletely, with TNBC.

Slide 61 · Homologous recombination deficiency in TNBC

DNA-repair abnormality

Genomic instability

Copy-number changes / rearrangements

High-grade TNBC phenotype

In familial tumors BRCA mutations may cause repair deficiency; Sporadic TNBC more often shows other mechanisms including BRCA1 silencing.

Slide 62 · TP53 and structural change dominate many TNBCs

TP53 is the only cancer gene mutated in the majority of TNBCs described in the source.

Other driving changes may involve rearrangements and copy-number variation.

Many TNBCs show marked cytologic atypia, brisk proliferation and necrosis.

A high burden of genome damage helps shape tumor immunogenicity.

Slide 63 · Genome instability can expose tumor neoantigens

Genomic instability

Altered tumor proteins

Neoantigen formation

Immune-cell recruitment

This mechanism helps explain prominent immune infiltration in many high-grade TNBCs.

Slide 64 · High-grade TNBC frequently engages immunity

Tumor neoantigens can stimulate immune recognition.

Some triple-negative tumors contain conspicuous tumor-infiltrating lymphocytes.

Tumor immune evasion can occur despite immune-cell recruitment.

Biological immune responsiveness provides a rationale for immunotherapy in appropriate settings.

Slide 65 · Not every triple-negative cancer is aggressive

Some special histologic types are triple-negative yet behave favorably.

The low-grade subset is morphologically and genetically distinct from common high-grade TNBC.

Biomarker negativity does not substitute for histologic classification.

Adenoid cystic, secretory and low-grade adenosquamous examples.

Slide 66 · Invasion is a biological paradox

Many genomic alterations in invasive breast cancer are detectable in carcinoma in situ.

No universal invasion-specific genomic change has been identified.

An invasive transition cannot be explained by driver acquisition alone.

Microenvironmental interactions are plausible determinants of basement membrane breach.

Slide 67 · Normal tissue integrity is cooperative

Lumen

Luminal epithelial cells

Inner epithelial ring

Myoepithelial cells

Outer epithelial layer

Basement membrane

Structural boundary

Stroma / matrix

Local support environment

Schematic transverse model: Normal barrier integrity depends on multiple interacting cell compartments.

Slide 68 · One route toward basement membrane failure

Preserved epithelial boundary

Proposed disruption in some lesions

In situ neoplastic epithelium

Stroma / extracellular matrix

In situ neoplastic epithelium

Stroma / extracellular matrix

Schematic hypothesis: Myoepithelial depletion and focal basement membrane defects may facilitate invasion.

Slide 69 · Cancer-associated fibroblasts support progression

Activated stromal fibroblasts can facilitate tumor-cell adhesion.

Extracellular matrix remodeling alters mechanical and signaling interfaces.

Fibroblasts may support a locally immunosuppressive environment.

Tumor and stroma can mutually reshape the niche during progression.

Slide 70 · Immune evasion can be locally engineered

Tumor PD-L1 expression

Checkpoint engagement

Reduced antitumor response

Immune escape

The source cites upregulation of PD-L1 as one possible mechanism among several.

Slide 71 · Microenvironment integrates three barriers

Physical

Basement membrane

Preserves epithelial boundaries

Biochemical

ECM and fibroblasts

Modulates invasion-associated signals

Immunologic

Immune cells / PD-L1

Constrains or permits tumor survival

Invasive behavior emerges from interactions, not a single isolated molecular switch.

Slide 72 · Major breast cancer pathways: Synthesis

Feature

Low-grade luminal

High-grade luminal / HER2 / TNBC

Precursors

Often recognizable

Earlier stages poorly defined

Genomics

1q gain / 16q loss

Greater structural complexity

Key signaling

ER / PI3K

Proliferation, HER2 or HR defect

In situ link

Low-grade DCIS / classic LCIS

High-grade DCIS

Slide 73 · Case: A low-grade luminal evolutionary pattern

A biopsy shows a monomorphic ER-positive ductal proliferation with limited low-grade architectural atypia. Molecular evaluation finds gain of 1q and loss of 16q.

Interpret:

Which evolutionary route is most consistent?

Why does atypia not prove inevitable invasion?

Slide 74 · Case: Inherited repair vulnerability

A patient carries a pathogenic germline BRCA1 variant. The carcinoma is high grade and triple-negative; Tumor cells show impaired homologous recombination.

Interpret:

Which inherited-somatic sequence can establish repair deficiency?

Why can PARP inhibition be effective?

Slide 75 · Case: Amplification and signaling

An invasive high-grade breast carcinoma shows strong HER2 protein expression and increased ERBB2 gene copies.

Interpret:

What genomic mechanism explains the phenotype?

Which downstream pathways mediate growth advantage?

Slide 76 · Mechanisms to retain

The initiating event and epithelial context influence tumor phenotype.

Low-grade and high-grade trajectories differ but can intersect.

BRCA-linked homologous recombination, estrogen–ER signaling and HER2 amplification are distinct pathogenic axes.

Microenvironmental remodeling and immune escape help explain the transition to invasion.

Slide 77 · Primary reading

Robbins, Cotran & Kumar

Pathologic Basis of Disease, 11th edition (2026)

The Breast — pathogenesis of breast cancer, including the familial and sporadic pathways.

Source locators, extraction boundaries, and visual provenance are recorded in the speaker notes.