Breast cancer ocure with involves genetic alterations of epithelial cell DNA, resulting in progressively more invasive and malignant somatic cells.

This disease is clearly the result of a complex, poorly understood multistep cancerogenecity process.

Etiology FactorsEtiology Factors

**ChemicalsChemicals

**Radiation Radiation

**RetrovirusesRetroviruses**Environmental factorsEnvironmental factors**Family history diseaseFamily history disease**genetic alterationsgenetic alterations

Risk Factors for Breast Cancer:Risk Factors for Breast Cancer:

Factors are increased risk :

*Increasing age,

*Family history,

*Exposure to female reproductive hormones ( both endogenous and exogenous ),

*Dietary factors,

*Benign breast disease

*Environmental factors

Risk Factor Relative RiskRisk Factor Relative RiskAny benign breast disease Any benign breast disease ……………………………….………………………………. 1.5 1.5Postmenopausal hormone reolacement Postmenopausal hormone reolacement …………….. …………….. 1.51.5

Menarche at <121yr Menarche at <121yr Menopause at >55yrMenopause at >55yr 1.9 1.9Sedentary lifstyle , Lack of Exersise Sedentary lifstyle , Lack of Exersise ………………….…………………. 1,9 1,9Increased bone density Increased bone density …………………………………. …………………………………. 1,91,9Prolifrative breast disease without atypia Prolifrative breast disease without atypia ………………………… 2 2Age at first birth>32yr or nulliparousAge at first birth>32yr or nulliparous…………………… …………………… 2- 4 2- 4First degree relative with breast cancer 2- 4First degree relative with breast cancer 2- 4Postmenopausal obesity Postmenopausal obesity ……………………………………. ……………………………………. 2- 42- 4Personal history of endometrial or ovarian ca 2- 4Personal history of endometrial or ovarian ca 2- 4Significant radiation to chest Significant radiation to chest …………………………….. …………………………….. 2- 42- 4Increased breast density on mamogram Increased breast density on mamogram ……………………………… 2- 4 2- 4Upper socioeconomic class Upper socioeconomic class …………………………………. …………………………………. 2- 42- 4Old age Old age ………………………………………………………….. ………………………………………………………….. 4 4Personal history of breast cancer Personal history of breast cancer …………………………………………………… >4 >4Two first degree relatives breast cancer Two first degree relatives breast cancer ……………………………… 5 5Upper socioeconomic classUpper socioeconomic class………………………………….. ………………………………….. 2-42-4

Increase the Risk:Increase the Risk:

*Benign Breast diseases

*Previous breast biopsy

*Previous breast surgery

*Fibrocystic disease ?

Increase the Risk:Increase the Risk:

*Prior treatment for cancer

*Oncogenes

*Growth factors

Growth regulatory pathways in Breast.C.

*Insulin-like growth factor 1,2 (IGF)

*Epidermal growth factor (EGF)

*Estrogen receptor (ER)

*Transforming growth factor a,B (TGF)

*Platelet-derived growth factor (PDGF)

Age:Age:

Advancing age has an Advancing age has an enomrouse impact on the enomrouse impact on the incidence of developing incidence of developing breast cancer.breast cancer.

Age (yr) Risk--------------------------------------------------------- 25 1 in 19,608 30 1 in 2525 35 1 in 622 40 1 in 217 45 1 in 93 50 1 in 50 55 1 in 42 60 1 in 24 70 1 in 10 80 1 in 8 85 1 in 7

Age and breast cancer incidence

Age (years) RiskBirth to 39 1 in 23540-59 1 in 2560-79 1 in 15Birth to death

1 in 8

*Women with a late first pregnancy have a higher

risk. (> 32y)

*Exagenous hormones (DES) increases the risk.

*Oral Contraceptive?*Post menopausal estrogen replacement may affect the incidence of B.C.in a dose related fashion.

*Lactation may reduced risk of premenopausal B.C.

Endocrine factor

Endocrine factors:

*Hormonal regulation of the breast is important in the development of breast cancer.

*Early pregnancy and Oophorectomy lower the incedence.

*Late menopause and early menarche increase the incidence.

*Nulliparous women have a higher risk.

Alcohol:Alcohol:

increase the risk of breast cancers.increase the risk of breast cancers.An association between alcohol An association between alcohol consumption and breast cancer.consumption and breast cancer.

Famelial BreastFamelial Breast CancerCancer

Woman with a first degree Woman with a first degree relative relative with breast cancer iswith breast cancer is aboutabout two to three timestwo to three times more likely to develop the more likely to develop the disease then a woman with a disease then a woman with a negative family historynegative family history..

Three subgroups with different risks of B.C.Three subgroups with different risks of B.C.

1-Turly hereditary 5-8%1-Turly hereditary 5-8%YoungerYounger , , bilateral and other tumors.bilateral and other tumors.

2-Intermediate risk2-Intermediate riskEarly first menstrual, fat body.Early first menstrual, fat body.

3-The risk is identical to 3-The risk is identical to general population.general population.

Diet:

High dietary fat intakeLow soyHigh caloric intakeObesity

Potentially protective dietary factorsinclude the intake of vitamins A, C, & E.Beta carotene and high fiber diet have redused the risk of Breast Cancer.

Genetic alterationsGenetic alterations

BRCA1 (17)BRCA1 (17)P53 gene (17)P53 gene (17)BRCA2 (13)BRCA2 (13)

BRCA1 (17)BRCA1 (17)

Autosomal dominant.Suppressor P 1863 amino acids.Tumor suppressor gene.Familial breast and ovarian cancer.63% risk of ovarian cancer.85% risk of breast cancer.

BRCA2 (13)BRCA2 (13)

Tumor suppressor gene

87% risk of breast cancer.

P53P53

-Tumor suppressor gene-Role in: DNA replication. Transcription. Cell cycle control.-Inhibits transformation of cells by myc and ras.

Hereditary Breast and Ovarian Cancer SyndromeHereditary Breast and Ovarian Cancer Syndrome.

*Mutation of the BRCA1 or BRCA2 genes

*The lifetime risk of breast cancer was 87% by age 70.

*The cumulative risk of Ovarian cancer was 44% by age 70.

*The relative Risk of colon cancer4.11 and

*Prostate cancer 3.33 (RR)

Family history and risk of breast cancer  

Relative risk estimate (95 percent CI)

Any family history 1.9 (1.7-2.0)

Degree of relatedness:

First degree (mother, sibling, child) 2.1 (2.0-2.2)

Second degree (grandmother, aunt) 1.5 (1.4-1.6)

Number of relatives:

One first degree 2.1 (2.0-2.2)

Two first degree 3.6 (2.5-5.0)

Age of relatives breast cancer :

First degree relative <50 2.3 (2.2-2.5)

First degree relative >50 1.8 (1.6-2.0)

First degree relative with bilateral breast cancer   

9.8 (4.0-24.9)

First degree relative with ovarian cancer    

1.27 (0.91-1.77)

Major breast cancer susceptibility genes

GeneAssociated syndrome

Chromosome site

Gene frequency

Gene penetrance for breast cancer

BRCA1 HBOC 17q21 Rare Very high

BRCA2 HBOC 13q12-13 Rare High

p53 Li-Fraumeni 17q13.1 Very rare High

PTEN Cowden 10q22-23 Very rare High

ATM Ataxia-telangiectasia (heterozygotes)

11q22-23 Common Low to moderate

STK11 Peutz-Jeghers 19p13.3 Very rare High

HBOC: Hereditary breast ovarian cancer syndrome.

Family histories breast ca ( Lif time Risk )

Mother pre 0.18-0.27 post 0,18-0.27

Sister pre/bil 0.56 pre/unil 0.08

Mother&Sister both pre,1bil 0.51 both pre,uni 0.33 1pre,1post, 1bil 0.23 both post, 1 bil 0.28Two sisters both pre,1bil 0.50 both pre, both uni 0.18 1pre,1post,1bil 0.11Mother & grandmother bothpre/1pre, 1post/both post. 0.27Mother & aunt both pre/1pre,1post/both post 0.14

Li-Fraumeni or SBLA SyndromeLi-Fraumeni or SBLA Syndrome

**Autosomal- dominant syndromeAutosomal- dominant syndrome

**Breast ca & other malignancyBreast ca & other malignancy soft tissue sarcomasoft tissue sarcoma brain tumorsbrain tumors LeukemiasLeukemias Lung cancerLung cancer Adernocortical tumorsAdernocortical tumors Osteosarcoma Osteosarcoma ChondrosarcomaChondrosarcoma

Muir’s SyndromeMuir’s Syndrome

*Autosomal dominant disorder

*Multiple skin tumors (sebaceous glands)

*Polyps and adenocarcinomas Large bowel Small intestine Stomach

cowden’s syndromecowden’s syndrome

* Hamartomatous lesion in

skin and oral cavity

* 74% with breast cancer

HER-2/neuHER-2/neu

*The class 1 growth factor-receptor tyrosine kinase

*Expressed in up to 30% of all breast cancers.

*Aquired

*Refractory to chemotherapy

For menFor men , , The androgen receptorThe androgen receptor gene has been implicated as a gene has been implicated as a causative factor.causative factor.

Androgene receptor gene is Androgene receptor gene is Normally controlled by a gene Normally controlled by a gene on the X chromosome. on the X chromosome.