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158 Cards in this Set
- Front
- Back
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where is the androgen receptor located?
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x chromosome
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What are the exons of the AR?
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N terminal domain (transcription regulation)
DNA binding domain Ligand binding domain |
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what is unique of the N terminal domain
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inhibitory domains (activating function 1)-- binds repressor proteins; binds to C terminus to inhibit itself
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where are steroid hormone receptors located?
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cytoplasm, where they are bound to chaperone proteins that keep them inactive
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what happens when steriod hormones bind to their cytoplasmic receptors?
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the nuclear receptor changes conformation, the chapertone protein is released and the receptor goes into the nucleus where it binds to AREs and activates transcription
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a missense mutation in the AR DNA binding domain
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will inhibit binding and can lead to androgen insensitivy syndrome
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why can amplification of the prostate specific antigen occur?
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enhancer elements that normally control AR get located upstream of the gene
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what does the androgen receptor interact with in the cytoplasm?
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src kinase, which will b/cm activated and lead to PIP pathway which will activate cell growth and survival
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what is the link btwn AR and prostate cancer
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AR activity is essential at all stages and phases of prostate cancer
-AR activity confers risk of prostate cancer -AR controls prostate cancer growth and susceptibility to apoptosis |
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TMPRSS2
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-its promoter is responsive to androgens
-it is located upstream to ERG gene -a deletion btwn TMPRSS2 places it and ERG under AR promoter |
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what is kennedy disease
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-c/b CAG repeats in N terminal of AR
-leads to spinal and bulbar atropaty -pts are also hypogonadal |
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what does CAG encode for
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glutamine
-high levels in CAG disease cause neurotoxcity |
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the length of CAG repeat
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makes a poorer functioning receptor ...
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which disorders are AR CAG repeats linked to
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prostate cancer
fertility, spermatogenesis bond density baldness BPH |
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clincal trial that gave men 5a reductase inhibitor (finasteride) had what outcome
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finasteride group had dcr incidence of prostate cancer vs placebo
-finasteride group had higher formation of more aggressive prostate cancer vs placebo |
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clinical study that used dutasteride to prevent prostate cancer had what outcome
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-lower incidence of low grade cancer in tx group vs placebo
-same incidence of aggresive cancer in tx group |
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what does the gleason test (which evaulates the prognosis of prostate cancer) show
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death from prostate cancer is significant at higher grades
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what was the outcome of tx prostate cancer with hormones and then surgery
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no effect on prognosis
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what is the action of Goserelin
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GnRH agonist
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what was the outcome of tx pts with radiation therapy and goserelin
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better outcome than radiotherapy alone
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the removal of androgens has what effect on prostate cells
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it induces apoptosis as evidence by incr in BAX and BID
-leads to loss of VEGF |
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what effect does radiation have in tx prostate cancer
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it induces apoptosis of vascular epitheial cells
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where does prostate cancer typically spread
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bone
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what was the outcome of early ADT (androgen deprivation therapy) in tx prostate cancer
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-started early, it dcr the motality from prostate cancer
-started early, overall mortality does not dcr (ADT is assoc with osteoporosis, hrt disease) |
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what is nilutamide
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an androgen receptor blocker
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what was the outcome of the clinical trial that used nilutamide (an AR blocker)
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it has an 8-10% reduction in prostate cancer mortality
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what happens to the AR in caustrate resistant prostate cancer
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it gets reactivated
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what was the outcome of the experiment that looked at the difference btwn gene expression in androgen dependent and androgen independent PC?
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the androgen receptor was overexpressed
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what happens if you overexpress AR in PC cells
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-you can hypersensitize cell to androgens
-you are sensitive to biva |
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what changes occur in prostate cancer cells deprived of androgens
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-they upregulate androgen receptors
-they acquire mutations making them insensitive to the drug that prevented androgen from binding to the AR |
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what happens to scr in prostate cancer that b/c androgen independent
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it is incr in androgen independent prostate cancer and phosphorlayes androgen receptor
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how does androgen signaling activity vary from bening to metastic cancer
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androgen signaling is lowest in metastatic PC ; cancer selects only the functions of AR that leads to cell proliferation via oligoubiquination of AR that allows it to select certain gene targets
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cancers can make hormones their self
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B catenin make androgen more sensitive
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when does breast development begin
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5th week with thickening of epidermis along the milk line (mamally ridge)
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what is the fate of the mammary ridge?
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it involutes from groin to chest
-if it doesn't invole it laeds to supernumerary breast (polythelia) |
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what is the effect of testosterone on breast development
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leads to a downward growth of epitheilum into stroma and arborization of solid ductal structures
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how dow breast ducts form
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via canalization of epithealial cords during last 2 mths of gestation
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what are lactiferous ducts
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the main ducts that emerge from nipple; proximally they arborize in a tree like fashion until the terminal duct lobular unit forms
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what is the mammary ridge
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a thickening of epidermis that initially extends from the axilla to groin
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what is the significance of the terminal duct lobular unit
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it promotes lesions
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each lactiferous duct produces a
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segment or lobe of the breast that are independent of each other
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what are the components of the TDLU
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-extralobular terminal duct (ETD)
-intralobular terminal duct (ITD) -ductules/acini -intralobular stroma -extralobular stroma |
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what structures are present in the infant's breast at birth
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duct composed of 2 cell types: luminal cell and myoepitheial (basal cell)
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functional of myoepitheial cell
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contract to secrete products during lactation
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what happens to female breast during menarchy
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lobules develop from GH, progesterone, estrogen
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what is the most common breast lesion
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fibrocystic changes
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what are fibrocystic changes?
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miscellaneous changes that occur in the breast involving ducts, lobules and stroma
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what changes can affect breast lobules
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atrophy
sclerosis hyperplasia |
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what is the clinical incidence of fibrocystic change in females?
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40-50%
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what is the pathological (microscopic) incidence of fibrocystic changes?
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60-80%
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what area of the breast does fibrosis affect?
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extralobular area
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what area of the breast does cysts affect?
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duct (dilation)
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what area of the breast does apocrine metaplasia affect?
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the skin/sweat like structures
(the breast is a modified sweat gland) |
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what is adenosis
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enlargment of the TDLU
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what is sclerosis adenosis
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sclerosis and enlargment of the TDLU
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what area of the breast does papillomatosis (epitheial hyperplasia) affect?
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the luminal cells which undergo hyperplasia
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what are fibrocystic changes of the breast?
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fibrosis
cysts aprocrine metaplasia sclerosing adenosis epithelial hyperplasia |
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blue domed area on breast pathology represents
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cyst
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high density mammograms with incr fibrosis...
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incr risk of breast cancer
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non invasive lesions
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have ductules and lobules lined by myoepitheial cells
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proliferative cyst disease without atypia
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-incr risk of breast cancer
-cells can transform and give rise to carcinoma of breast |
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which lesions of the breast do not incr risk of breast cancer
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hyperplasia (mild, 2-4 cells)
apocrine metaplasia cysts duct ectasia fibroadenoma |
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which lesions of the breast lead to a slight incr in risk of breast cancer
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moderate or florid hyperplasia (both ductal and lobular) aka proliferative cyst disease without atypia
papilloma adenosis |
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which breast cancer lesion leads to a moderately (5x) incr risk of breast cancer
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atypical ductual and lobular hyperplasia
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what does atypia mean?
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resemblance to low grade in situ cancer
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why is atypical ductal hyperplasia (ADH) refered to as a borderline lesion?
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it meets some but not all of the criteria for ductal carcinoma in situ
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what is a classic feature of low grade CIS?
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-regular lumens within ducts
-cells that do not overlap -cells with a dcr nucleus cytoplasm ratio |
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risk of developing invasive breast cancer from in situ ductal carcinoma
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8x; unilateral
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risk of developing invasive cancer from atypical ductal hyperplasia
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4-5x; bilateral
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when is the risk for developing invasive carcinoma greatest?
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in first decade following dx
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pts with ADH wih fhx of breast cancer have what risk of developing invasive cancer
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8-10x
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30% of pts with ADH on needle biopsy...
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have cancer on excision
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what are benign neoplasms
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-fibroadenoma
-intraductal papilloma -cystosarcoma phyllodes |
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what is the most common benign tumor of the breast
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givroadenoma
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what is the epi of fibroadenoma
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-usually appears in young women
-peak incidence 3rd decade of life |
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what is a fibroadenoma
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a benign fibroepitheial tumor with a storma component that is rarely associated with carcinoma
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what is a complex fibroadenoma?
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a fibroadenoma with cystic change; the only fibroadenoma that icr risk of breast cancer
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what are intraductal papillomas
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-benign papillary neoplasm within a duct
-can occur centrally in lactiferous duct or peripherally in TDLU |
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intraductal papillomas that occur ... have no incr risk of developing breast cancer
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centrally
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what is the most common cause of bleeding from the nipple
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rupture of a central intraductal papilloma
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what is the neoplastic component in cystosarcoma phyllodes
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the stroma
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what is cystosarcoma phyllodes
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a fibroepithelial neoplasm of variable malignant potential
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when cystosarcoma b/cms independent of the epithelium supporting it, it ..
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degenerates inot a frank sarcoma with metastasis to lung and distant organs
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the majority of cystosarcoma ..
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can be cured by complete excision
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what is the peak incidence of cystosarcoma
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50yrs old
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what is a sarcoma?
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a malignant neoplasm that arises from mesenchymal cells
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how are DCIS usually detected?
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by association with microcalcifications
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how do you classify a cytosarcoma phyllode
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the nuclei of the mitotic figures
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what are teh epithelial derived malignant tumors
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-intraductal carcinoma
-in situ carcinoma -invasive ductal carcinoma -invasive lobular carcinoma |
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most carcinoma of the breast recapitulates ...
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luminal or ductal epithelium
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what are characteristics of lobular breast carcinoma
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small size
loss of E cadherin probably precursor cells for estrogen receptor + cells |
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what is a ductal carcinoma in situa
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neoplastic transformation taht recapitulates ductal epithelium within the duct, bounded by myoepithelium cells, non invasive and cannot metastasize
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when is a carcinoma ductal?
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when it is well circumcribed and there is myoepithelial cells around it
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what are the histological patterns of DCIS?
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comedo, solid, cribiform, clinign, and papillary
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what predicts the likely of recurrence of in situ cancer or invasion
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nuclear grade
extent of duct involvement |
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what is the risk of developing invasive carcinoma in a pt that has DCIS
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8-10x, ipsilateral
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how is DCIS detected?
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microcalcification on mammogram
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what are features of high grade DCIS
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a lot of mitotic figures
high nuclei/cytoplasm ratio pleimorphic figures |
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what are features of low grade DCIS
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dcr n/c ratio
rarely nicrotic low mitosis rate |
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what is paget's disease of the breast
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a type of DCIS that extends to the epidermis and involves the nipple and areola
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what is the typical classifcation of paget's disease breast cell
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HER2 overexpression
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what is the typical presentation of paget's disease
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nipple dischager, crusting or excoritation or excezma changes of the nipple
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how are invasive ductal carcionomas classivied
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NOS-- no special type (70-80%(=)
special type: invasive lobular medullary carcinoma colloid carcinoma tubular carcinoma |
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what are invasive ductal carcinomas
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an infiltrative malignant epithelial process resembling ductal epithelium; most common breast carcinoma
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which carcinoma occurs commonly in pts with BRAC1 mutations
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medullary carcinoma
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what is the prognosis of medullary carcinoma?
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good
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what is the histology of medullary carcinoma
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extensive lymphoplasmacytic infiltrate
undifferntiated high mitotic rate resembles brain germ cells |
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how is inflammatory breast cancer defined?
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clincally-- more than 1/3 of the skin surface is erythematous, peau de orange
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pathology findings in inflammatory carcinoma
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carcinoma w/in ductal lymphatics
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lobular carcinoma in situ can occur
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in ducts or lobules
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what is lobular carcinoma in situ
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neoplastic transformed epitheial cells of small size that loos E cadherin and line termina ducts ans acini
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what is the usual classification of LCIS
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ER/PR +, HER2 -
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what is the risk of developming invasive cancer in pts with LCIS
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6-9x, bilateral
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most of the cancers that develop in pts with a hx of LCIS are ..
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ductal, and thus LCIS is a risk factor for developing invasive cancer
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what is the risk of developing a serial progression of LCIS to invasive cancer
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1/4
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how are LCIS tx?
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NOT surgically excised
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what are prognostic factors of breast cancer
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size of primary tumor
lymph node involvement and extent grade histologic type ER/PR |
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luminal A breast cancer
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resembles normal luminal epithelium
ER+ low grade excellent prognosis low p53 mutation rate |
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luminal B
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ER+ but less than lumianl A
higher grade worse prognosis some HER2+ more mutations |
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what is stage 0 breast cancer
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DCIS-- cancer cells are present in the lining of a breast lobule or duct but they have not yet spread to the surrounding fatty tissue
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what is stage 1 breast cancer
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tumor is less than 2 cm
no lymph nodes involved |
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stage II breast cancer
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tumor is 2-5 cm
less than 4 lymph nodes are involved |
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stage III breast cancer
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locally advanced
tumor may be larger than 5cm or more than 4 lymph nodes involved |
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stage IV breast cancer
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metastatic
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at what stage do most women with breast cancer present
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at stages 0, 1, 2
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what are risk factors for breast cancer
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alcohol
BMI HRT long estrogen exposure age benign breast disease |
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what are the changes from benign breast disease to in situ
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hyperplasia (1.5xs)
--> atypia (4x) --> in situ (10x) |
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what is the percentage of hereditary breast cancer
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5-10%
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what is the persentage of sporadic breast cancer
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70-80%
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what factors incr the likelihood of having BRCA mutation
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-multiple cases of early onset breast cancer
-ovarian ca -breast and ovarian ca in same women -bilateral breast cancer -ashkenazi jew -male breast cancer |
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what confers the greatest risk of breast cancer
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mammographic density
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what confers an intermediate risk of breast cancer
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family hx
benign breast disease adenosis (sclerosing or fibrosis) papilloma |
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clinical trials show a mastectomy ...
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has same survial as lumpectomy + radiation therapy
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chemotherapy in pts older than 50
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has a reduced decline in mortality
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prognostic factors
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estimate outcome independent of systemic tx
reflect tumor biology, i.e. how aggresive tumor is tells you who should be tx |
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predictive factors
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reflect a relative resistance or sensitivity to specific therapy
tells you what specific tx should be offered to pt |
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what are strong prognostic factors
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TNM stage
axillary nodal status size |
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what are moderate breast cancer risk factors
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tumor grade
lymphatic or vascular invasion |
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what are weak breast cancer factors
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ER and PR cnotent
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what are predictive factors for breast cancer
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age
ER status grade HER2 |
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what are the aromatase inhibitors
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aromasin
letrozole anastrozole |
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what is an estrogen receptor blocker or partial agonist
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tamoxifen
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aromatase inhibitors are only beneficial in
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postmenopausal women
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what is the effect of dcr estrogen activity on cancer cells
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dcr cellular proliferation
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what is the oxford overview data of tamoxifen
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effective in all homone receptor positive women
effective regardless of age, stage, or tumor grade tx for 5 yrs |
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what are side effects of tamoxifen
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DVT
incr risk of stroke incr risk of endometrial cancer |
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side effects of aromatase inhibitors
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bone loss
joint pain |
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what the chemotheraputic agents
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anthracyclines (Adriamycin/eiprubicin)
taxanes (taxol/taxotere) cyclophosphamide 5FU carboplatin |
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what is the oxford overview data of chemotherapy
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-polychemotherapy is better than single agent
-anthracycline based therapy is superior to non antrhacycline regiments -all women benefit but younger women with poorly differentiated, hormone receptor negative tumors are more likely to benefit |
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what is trastuzumab (herceptin)
tras-to-zum-ab |
HER2 (human epidermal growth factor receptor) antibody
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what is the effect of HER2 overexpression
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incr cell proliferation
incr cell migration resistance to apoptosis |
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trastuzumab should be used with
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chemotherapy
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what is the major side effect of herceptin
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cardiomyopathy
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how can breast cancers be classified
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basal like (triple -)
HER/EB2 luminal |
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what is an oncotype test
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it looks at 16 cancer and 5 reference genes and sees if they are active or inactive and stratifies their risk
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what are the goals of therapy for metastatic breast cancer
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improve overall survival
improve time to progression improve sx improve quality of life |
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what are tx options for metatastic breast cancer
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endocrine therapies
chemotherapy novel therapy (herceptim) supportive (surgery, radiation, bisphosphonates) |
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how are pts with metatastic breast cancer monitored
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tumor markers, i.e.CEA
imaging circulating cells |
