The Breast

Question 1

what are the 2 major structures of the breast?

Answer 1

ducts (connect lobules to nipples)
lobules

Question 2

what are the 2 types of breast epithelial cells?

Answer 2

luminal -In center

myoepithelial- around luminal

Question 3

when do the breast ducts and first development of lobules start?

Answer 3

puberty - ovarian estrogen and progesterone induction

Question 4

What are the two types of stroma ?

Answer 4

• Interlobular
• Intralobular

Question 5

when do breasts fully develop and what contributes?

Answer 5

pregnancy: progesterone, prolactin → permanent ↑ in lobule #/size

oxytocin → myoepithelial differentiation and proliferation

Question 6

Following lactation total breast size decreases due to?

Answer 6

due to apoptosis of epithelium and lobule atrophy

Question 7

what happens to breast tissue after menopause?

Answer 7

atrophy of lobules & ducts
↓ in fibrous connective tissue
↑ adipose tissue content

Question 8

where do carcinomas and fibroadenomas happen in the breast?

Answer 8

carcinomas: lobules & ducts
fibroadenomas: intralobar stroma
- Stroma: is the part of a tissue or organ with a structural or connective role. It is made up of all the parts without specific functions of the organ - for example, connective tissue, blood vessels, nerves, ducts, etc. The other part, the parenchyma, consists of the cells that perform the function of the tissue or organ.

Question 9

what are the 3 classes of benign breast lesions and examples of each?

Answer 9

1. non-proliferative:
   - simple breast cyst (fluid filled mass, not proliferative- no risk of malignancy)
2. proliferative without atypia:
   - fibroadenoma

→small increased risk of developing breast cancer in certain sitauations

3. atypical hyperplasia: (proliferative with atypia)
   - atypical ductal & lobar hyperplasia (substantial ↑ risk of breast cancer)

Question 10

Simple Breast Cyst:

Can it become malignant?

Where does the fluid filled masses come from?

Answer 10

• no risk of becoming malignant because its non-proliferative
• fluid filled masses derived from the terminal duct lobular unit

Question 11

what kind of tissue is in a fibroadenoma?

Answer 11

glandular and fibrous

Question 12

what kind of fibroadenomas are associated with increased cancer risk?

Answer 12

complex fibroadenomas slight ↑ risk with multi centric proliferative changes due to calcification

-usually only w. family hx

Question 13

what are the 2 likely etiologies of fibroadenomas?

Answer 13

Hormonal:
-estrogen, progesterone, lactation during pregnancy

-EGF (human epidermal GF) receptors on surface: respond to EFG and GH

Genetics: MED12 gene

Question 14

Simple Fibroadenoma

Composition?

is there an increase in cancer risk?

Answer 14

• benign, solid tumors containing glandular as well as fibrous tissue
• majority: no increased risk of dev. breast cancer

Question 15

What is Estrogen and where does it come from?

Answer 15

steroid hormone derived from androgenic precursors androstenedione and testosterone via aromatization

Question 16

what are the 3 kinds of naturally occurring estrogens?

Answer 16

estrone (E1): predominant form of circulating estrogen after menopause

17 ß-estradiol (E2): found primarly in premenopausal women and produced by theca and granulosa cells in the ovary

estriol (E3): Is the estrogen the placenta makes during pregnancy

Question 17

ER-α

predominantly found?

sustained stimulation and activation can lead to?

Answer 17

Predominant ER receptor in the uterus & mammary gland

-sustained stimulation and activation of receptor leads to ↑ breast & endometrial cancer risk

Question 18

ER-ß

Prodominantly expressed in ?

affect on cancer?

Answer 18

• ovary, prostate (b - boys have it too)
• -activates anti-proliferative and pro-apoptotic pathways in many cancer cells

Question 19

G-Protein Coupled Estrogen Receptor (GPER)

mediates ?

regulates ?

Answer 19

G-Protein Coupled Estrogen Receptor

mediates rapid estrogen signaling, expressed in ovary
→regulates follicle maturation

Question 20

HER2 Oncogene

Encodes for?

Function?

Answer 20

encodes HER2 receptor:

controls cell growth, differentiation, angiogenesis (activates GF pathways)–cell survival

Question 21

what percent of breast cancers express overamplification of HER2?

Answer 21

20%

Question 22

what are the 3 biologic subgroups of breast cancer?

Answer 22

1. ER positive (80%)
2. HER positive (20%)
3. Triple Negative (ER-, PR-, HER2-)

Question 23

what should all females <60yo with triple negative breast cancer be tested for?

Answer 23

BRCA mutations

Question 24

what is HER2 and ER cross-talk?

Answer 24

-complex, bi-directional

treating only one of them if they are both positive amplifies the untreated one → resistance to therapy

Question 25

"Drivers" of cell proliferation and survival in majority of human breast cancers?

Answer 25

Estrogen Receptors (ER) & HER2 signaling pathways

Question 26

\>95% of breast carcinomas are what kind of tumors?

Answer 26

adenocarcinomas

Question 27

what are the 2 in situ breast carcinomas? (in place)

Answer 27

**ductal (most common)** lobular

Question 28

what are the 2 invasive breast carcinomas?

Answer 28

infiltrating **ductal** 76% invasive lobular 8%

Question 29

What is a Ductal Carcinoma In Situ (DCIS)?

Answer 29

A proliferation of abnormal cells confined within the mammary ductal system -no invastion

Question 30

what are the 3 nuclear grades of ductal carcinoma in situ (DCIS) and traits of each?

Answer 30

## Footnote 1. high grade: **no ERs or PRs**, _high_ proliferative rate, _overexpression of HER2 oncogene,_ P53 mutation, angiogenesis (HER2+) 2. intermediate grade 3. low grade: ER and PR positive, low proliferative rate (EPR+) all: +/- necrosis

Question 31

what are the 3 grades of infiltrative ductal breast carcinoma?

Answer 31

1. well-differentiated (G1): uniform cells, no mitosis 2. moderately-differentiated (G2): some glandular differentiation, moderate mitotic activity 3. poorly-differentiated (G3): no gland differentiation, significant mitotic activity \*\*\*\*the more poorly differentiated the INCREASE in chaotic architexture of cells

Question 32

Gold standard of dx for **invasive ductal breast carcinoma?**

Answer 32

biopsy

Question 33

what are most familial breast cancers?

Answer 33

80-90% BRCA1 & BRCA2

Question 34

what do normal BRCA genes do?

Answer 34

produce proteins to help repair DNA

Question 35

what are the major risk factors for sporadic (don't involve BRCA genes) breast cancer?

Answer 35

hormone exposure and age age (at menarche and menopause, reproductive hx - more preg. less risk, breastfeeding, and exogenous estrogen exposure) gender radiation exposure/chemicals with estrogen like effects estrogen (↑ breast growth during puberty/menstrual cycles/pregnangy --\> ↑ cells that can be cancerous)

Question 36

what are the 2 methods of computational investigation of DNA repair deficiency in sporadic breast cancer?

Answer 36

**BRCAness profile** -based on gene expression profiles between sporadic and familial tumors, _influences management and txs for **sporadic** breast and ovarian cancers_ _→very important to know to give your patient the best chance at survival_ **sample-specific BRCA score:** (homologous recombination DNA repair pathway)

Question 37

why should BRCAness and sample-specific BRCA scores be evaluated for sporadic breast cancers aka what is their clinical significance?

Answer 37

defects in HR DNA repair pathway are susceptible to alkylating chemo (causes DNA strand breaks) in ovarian cancer, ↑ BRCA score more sensitive to chemo, **better outcomes**