Hormones/Cancer

Question 1

oncogenic form of epidermal growth factor

Answer 1

HER2

Question 2

What are the five types of breast cancer?

Answer 2

Question 3

Two most common types of breast cancer and what makes them unique

Answer 3

Luminal A and Luminal B tumors express ER (ER positive, ER+) and thus are targeted by ‘endocrine therapies’, tamoxifen or aromatase inhibitors, e.g., letrozole. Luminal B is more proliferative breast tumor subtype than Luminal A and shows higher expression of DNA proliferation markers

Question 4

What does tripple negative mean

Answer 4

the breast tumor does not express the major 3 breast tumor markers: no ER, no PR, no HER2/ERBB2

Question 5

How does the estrogen receptor work

Answer 5

It is a ligand-activated transcription factor that binds DNA at specific sites and upregulates gene transcription in response to estrogen binding to the ligand binding domain. From N-to C- terminal (left to right) we see AF-1 = activation function 1, a DNA binding domain (DBD), a black box that is a flexible hinge region, and in blue the ligand binding domain (LBD) with AF-2 = activation function 2. AF-2 is active when estrogens bind the LBD.

Question 6

How does estrogen lead to breast cancer

Answer 6

Esterogen binds to ER, ER stimulates the transcription of genes involved in cell growth and division including genes that regulate cell cycle progression, e.g., cyclin D1

Question 7

Where does most breast cancer begin

Answer 7

Most breast tumors originate in breast epithelial cells in the lining of the ducts, from luminal epithelial cells, and progress to DCIS (ductal carcinoma in situ), then to invasive carcinoma, and, with further molecular changes, to metastatic carcinoma

Question 8

What is SERD and example

Answer 8

Selective ER down-regulators- Fulvestrant (Faslodex®; ICI 182,780). Fulvestrant competes with E2 and other estrogens for binding to the ligand binding domain of ER and blocks estrogen action while also causing ER to be degraded (after ubiquitinylation) in the proteosome

Question 9

What is E2

Answer 9

Estradiol

Question 10

What is different about raloxifene versus tamoxifen since both are SERMs?

Answer 10

Raloxifene does not act like an ER agonist in the uterus, so it does not increase the risk of endometrial cancer.

Question 11

What is the purpose of Aromatase Inhibitors

Answer 11

AIs inhibit the conversion of androgens into estrogens, good for the treatment of ER+ breast cancers

Question 12

What is the preferred AI in clinical use

Answer 12

Letrozole

Question 13

_______ is a risk factor for breast cancer in postmenopausal women

Answer 13

Obesity is a risk factor for breast cancer in postmenopausal women

Question 14

Why does increased fat lead to more estrogen

Answer 14

Aromatase is expressed in stromal fibroblasts. Aromatase expression is increased by proinflammatory adipokines secreted from adipocytes, which are in the breast, so with obesity and increased adipocyte mass (size and number), a proinflammatory environment leads to increased aromatase to convert androgens to estrogens to activate ER in adjacent breast epithelial cells. More activated ER means an increase in pro-proliferative gene transcription.

Question 15

What is acquired endocrine resistance?

Answer 15

de novo resistant to endocrine therapies, even if a tumor did express ER

Question 16

What is important about mutations in the ER LBD

Answer 16

mutations in the ER LBD can activate ER in the absence of estrogen, inhibit estrogen and tamoxifen binding, and thus are involved in endocrine-resistant metastatic breast cancer.

For normal ER, when estrogen (E2) binds the ER, it dimerizes and recruits coactivators (CoA, green). However, in the case of the point mutants where we see a single amino acid change, these mutations allow the mutant ER to assume a conformation that is active without binding estrogens, e.g., E2, and recuit coactivators.

Question 17

How are CDK inhibitors used in cancer treatment

Answer 17

Cyclin-Dependent Kinases (CDK) regulate the Cell Cycle. To inhibit cell proliferation, cell cycle progression is blocked by CDK4/6 inhibitors. CDK4/6 inhibitors (Abemaciclib, Ribociclib, and Palbociclib) are used in combination with AI or fulvestrant to treat patients with metastatic breast cancer for ER+/HER2- primary tumors.

Question 18

What is retinoblastoma (Rb)

Answer 18

Retinoblastoma Tumor suppressor protein (RB) is normally bound to the transcription factor (TF) E2F to prevent it from binding DNA, thus negatively regulate cell cycle and preventing cell replication.

Question 19

How do CDK4/6 relate to Rb

Answer 19

CDK4/6 are in a complex with cyclin D1 and when activated by extracellular signaling pathways, phosphorylate RB which inactivates RB. This allows E2F (a transcription factor) to dissociate from the phospho-RB, bind DNA, and stimulate the transcription of genes for G1 to S cell cycle progression. Thus blocking CDK4/6 would stop cell proliferation

Question 20

What is PI3K

Answer 20

The phosphatidylinositol-3-kinase (PI3K)-AKT-mTOR cellular pathway controls cellular processes including metabolism, proliferation, survival, and migration. This pathway is one of the most frequently dysregulated pathways in metastatic breast cancer (as well as other cancers). The pathway is activated by mutations and overexpression of genes.

Question 21

Example of PI3K inhibitor

Answer 21

Alpelisib (Piqray) is FDA-approved in combination with fulvestrant (SERD) for metastatic breast cancer in ER+/HER2- postmenopausal women.

Question 22

Mechanism of alpelisb

Answer 22

PI3K inhibitor alpelisb inhibits activated PI3K from phosphorylating and activating AKT. This blocks AKT from activating the Cyclin D1/CDK4/6 complex which blocks cell cycle progression.

Question 23

What is mTORC

Answer 23

mTORC1 is a component in the mTOR pathway and is a ser-thr kinase that phosphorylates S6K. In turn S6K, phosphorylates and activates ER, independent of estrogen binding.

Question 24

What is the mTOR inhibitor and when is it used

Answer 24

Everolimus and is used as a secondary treatment for ER+/HER2- metastatic breast cancer in PM women used in combination with AIs, including exemestane even though the treatment is used for patients resistant to AIs- the theory is that Everolimus will resenstize cells to AIs (and keep estrogens low).

Question 25

What do hormone therapies in premenopausal women target

Answer 25

Hormonal therapies in premenopausal women disrupt the Hypothalamus-Pituitary-Ovarian axis

Question 26

GnRH analog and how it works

Answer 26

Goserelin (Zoladex) is a GnRH/LHRH analog inhibits GnRH signaling, thus decreasing LH and FSH and in turn, E2 synthesis and release from the ovary. However, Goserelin transiently increases LH, FSH (and downstream from the ovary E2). This is referred to as a “flare”, but high doses over time desensitize the pituitary which then stops gonadotropin production. Goserelin reduces the risk of ovarian or tubal cancer.

Question 27

Women with stage I BrCa not warranting chemotherapy should receive endocrine therapy but not receive ovarian suppression. WHY?

Answer 27

Adverse effects of ovarian ablation therapy: Increased mortality: CV disease, Colorectal cancer, All types cancer combined; Detrimental impact on quality of life: vasomotor symptoms, sexual dysfunction, Osteoporosis and fractures

Question 28

What is BPH

Answer 28

Benign prostatic hyperplasia (BPH) is the noncancerous growth of the prostate gland due to over-proliferation of the stromal and glandular cells that is stimulated by dihydrotestosterone (DHT).

Question 29

Treatment for BPH

Answer 29

5alpha reductase inhibitors Finasteride and Dutasteride are used to treat BPH by decreasing DHT

Question 30

Why can DHT cause prostate growth

Answer 30

DHT binds the androgen receptor (AR) with high affinity allowing AR to dimerize, bind DNA, stimulate recruitment of coactivators and chromatin remodeling proteins, and upregulate the transcription of genes for cell growth in the prostate.

Question 31

What is ADT

Answer 31

Androgen deprivation therapy – considered castration

Question 32

What is the GnRH antagonist

Answer 32

Degarelix (Firmagon) produce no testosterone “flare”

Question 33

What are the SARMs and when are they used

Answer 33

Enzalutamide is used post-chemotherapy.

Apalutamide is used for patients with non-metastatic castration-resistant prostate cancer (CRPC)

Darolutamide was FDA approved 7/30/19 for non-metastatic CRPC

Question 34

SARMs mechanism

Answer 34

When AR is occupied by a SARM (red boxes), AR recruits corepressors and histone deacetylase complexes (HDACs) that deacetylate chromatin (Ac), thus condensing the chromatin, so that RNA pol II is not recruited. Thus PSA, and other androgen target genes (those that would stimulate prostate cancer cell growth and metastasis) are not transcribed

Question 35

What happens in CRPC

Answer 35

There is increased CYP17 and local androgen production - mutation ing LBD causing initiation of transciption in absence of androgen binding

Question 36

What is Abiraterone acetate

Answer 36

a CYP17 inhibitor that is approved for CRPC (pre- or post- chemotherapy) in combination with prednisone. It is referred to as an antiandrogen since is reduces androgen synthesis in prostate cancer, but unlike the SARMs, it does not compete with androgens for AR

Question 37

Why is prednisone given with abiraterone acetate

Answer 37

Inhibiting CYP17 with abiraterone acetate will reduce 17alpha-hydroxy-prepnenolone and DHEA. Thus,a patient taking abiraterone acetate for CRPC will need prednisone to supplement endogenous corticosteroids