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 Factors * Chemicals * Radiation * Retroviruses * Environmental factors * Family history disease * genetic alterations

Risk Factors for Breast Cancer Multiple factors are associat ed with an increase d risk of developi ng breast cancer, including increasin g age, family history, exposur e to female reproduc tive hormone s (both endogen ous and exogeno us), dietary factors, benign breast disease, and environ mental factors 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 Risk Any benign breast disease ………………………………. 1.5 Postmenopausal hormone reolacement …………… Menarche at 55yr 1.9 Sedentary lifstyle, Lack of Exersise …………………. 1,9 Increased bone density …………………………………. 1,9 Prolifrative breast disease without atypia …………… 2 Age at first birth>32yr or nulliparous …………………… 2- 4 First degree relative with breast cancer 2- 4 Postmenopausal obesity …………………………………… Personal history of endometrial or ovarian ca 2- 4 Significant radiation to chest …………………………… Increased breast density on mamogram ……………… 2- 4 Upper socioeconomic class ………………………………… Old age ………………………………………………………….. 4 Personal history of breast cancer ………………………… >4 Two first degree relatives breast cancer ……………… 5 Upper socioeconomic class ………………………………….. 2-4

Women with a late first pregnancy have a higher risk.Exagenous hormones (DES) increases the risk. Oral Contraceptive? Post menopausal estrogen replacement may affect the incidence of B.C.in a dose relatedfashion. Lactation may reduced risk of premenopausal B.C. Increase the Risk: * Benign Breast diseases * Previous breast biopsy * Previous breast surgery * Fibrocystic disease ?

Women with a late first pregnancy have a higher risk.Exagenous hormones (DES) increases the risk. Oral Contraceptive? Post menopausal estrogen replacement may affect the incidence of B.C.in a dose relatedfashion. Lactation may reduced risk of premenopausal B.C. 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: Advancing age has an enomrouse impact on the incidence of developing breast cancer.

Age (yr) Risk in 19, in in in in in in in in in in 7

Age and breast cancer incidence Age (years)Risk Birth to 391 in in in 15 Birth to death1 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: increase the risk of breast cancers. An association between alcohol consumption and breast cancer.

Famelial Breast Cancer Cancer

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

Three subgroups with different risks of B.C. 1-Turly hereditary 5-8% Younger, bilateral and other tumors. 2-Intermediate risk Early first menstrual, fat body. 3-The risk is identical to general population.

Diet: High dietary fat intake Low soy High caloric intake Obesity Potentially protective dietary factors include the intake of vitamins A, C, & E. Beta carotene and high fiber diet have redused the risk of Breast Cancer.

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

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) Tumor suppressor gene 87% risk of breast cancer.

P53 -Tumor suppressor gene -Role in: DNA replication. Transcription. Cell cycle control. -Inhibits transformation of cells by myc and ras.

Hereditary Breast and Ovarian Cancer Syndrome Hereditary 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 history1.9 ( ) Degree of relatedness: First degree (mother, sibling, child)2.1 ( ) Second degree (grandmother, aunt)1.5 ( ) Number of relatives: One first degree2.1 ( ) Two first degree3.6 ( ) Age of relatives breast cancer : First degree relative <502.3 ( ) First degree relative >501.8 ( ) First degree relative with bilateral breast cancer 9.8 ( ) First degree relative with ovarian cancer 1.27 ( )

Major breast cancer susceptibility genes Gene Associated syndrome Chromosom e site Gene frequenc y Gene penetrance for breast cancer BRCA1HBOC17q21RareVery high BRCA2HBOC13q12-13RareHigh p53Li-Fraumeni17q13.1Very rareHigh PTENCowden10q22-23Very rareHigh ATMAtaxia- telangiectasia (heterozygotes) 11q22-23CommonLow to moderate STK11Peutz-Jeghers19p13.3Very rareHigh HBOC: Hereditary breast ovarian cancer syndrome.

Family histories breast ca ( Lif time Risk ) Mother pre post 0, Sister pre/bil 0.56 pre/unil 0.08 Mother&Sister both pre,1bil 0.51 both pre,uni pre,1post, 1bil 0.23 both post, 1 bil 0.28 Two sisters both pre,1bil 0.50 both pre, both uni pre,1post,1bil 0.11 Mother & grandmother bothpre/1pre, 1post/both post Mother & aunt both pre/1pre,1post/both post 0.14

Li-Fraumeni or SBLA Syndrome * Autosomal- dominant syndrome * Breast ca & other malignancy soft tissue sarcoma soft tissue sarcoma brain tumors brain tumors Leukemias Leukemias Lung cancer Lung cancer Adernocortical tumors Adernocortical tumors Osteosarcoma Osteosarcoma Chondrosarcoma Chondrosarcoma

Muir’s Syndrome * Autosomal dominant disorder * Multiple skin tumors (sebaceous glands) * Polyps and adenocarcinomas Large bowel Small intestine Stomach

cowden’s syndrome * Hamartomatous lesion in skin and oral cavity * 74% with breast cancer

HER-2/neu * The class 1 growth factor-receptor tyrosine kinase * Expressed in up to 30% of all breast cancers. * Aquired * Refractory to chemotherapy

For men, The androgen receptor The 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.

Risk Factors for Breast Cancer Multiple factors are associated with an increased risk of developing breast cancer, including increasing age, family history, exposure to female reproductive hormones (both endogenous and exogenous), dietary factors, benign breast disease, and environmental factors.