Breast Cancer Flashcards
Nuclear receptors
= steroid receptors or lipid receptors
Cortisol production and binding
A glucocorticoid
Ligand for glucocorticoid receptor
Produced by adrenal cortex
Cortisol’s effects on the immune system
An important negative regulator of the immune system. Suppresses the expression of pro-inflammatory genes in immunce cells, and activate the expression of anti- inflammatory genes. Potent agonists of GR (such as prednisone) are therefore used to treat many different conditions when it is important to suppress the inflammatory response, such as allergy or autoimmune disease.
Cortisol effects on metabolism
Cortisol in an important stress response hormone and is produced at higher levels in the fasting state. It reinforces the activty of glucagon and epinephrine to promote fuel mobilization. However, its effects are primarly a result of causing changes in gene expression.
For example, cortisol stimulates the expression of genes required for gluconeogenesis in the liver, increases the expression of hormone sensitive lipase in adipose tissue, and promotes muscle protein breakdown, to stimulate the release of amino acids to support gluconeogenesis.
Side effects of glucocorticoids given as anti-inflammatories
The use of potent agonists of GR to treat autoimmune disease is a double edged sword, as it can lead to side effects such as hyperglycemia, fat redistribution, and muscle atrophy, among other symptoms
Aldosterone
A mineralocorticoid
Ligand for the mineralocorticoid receptor
Produced by the adrenal cortex, acts almost exclusively on the kidneys
Progesterone
A progestin
Ligand for the progesterone receptor
Produced in ovaries, acts in female reproductive tract, breast, and brain
Functions of progesterone
Progesterone levels vary during the menstrual cycle, and it has important effects in regualting the lining of the uterus (endometrium). Its levels are also elevated during pregnancy. Progesterone plays important roles in breast development during puberty and pregnacy, and also regulates lactation. Many of the actions of progesterone require the action of estrogen, because estrogen regulates the expression of the progesterone receptor.
Testosterone
An androgen
Ligand of the androgen receptor
Produced by the adrenal gland in both men and women, and also the testis in men
Functions of testosterone
Testosterone is critical for development of the male reproductive organs as well as further development of male characteristics in puberty. Testosterone is also important for function of the prostate in adults and therefore the androgen receptor is an important drug target for treatment of prostate cancer. Androgens can also promote the growth of muscle and for this reason can be considered a type of anabolic hormone.
Synthesis of steroid hormones from cholesterol
Estradiol
An estrogen
Ligand of the estrogen receptor
Produced by ovaries and peripheral tissues, acts on female reproductive tract, breasts, brain
Functions of estrogens
Estrogen is important during puberty for development of the reproductive system and secondary sexual characteristics in females, and also regulates the biology of the endometrium and and breast during the reproductive cycle. Estrogen is important for expression of the progresterone receptor. Estrogen and progresterone work together to regulate proliferation and differentiation of the ducts and lobules of the breast during puberty, pregnancy and lactation.
Because many breast cancers are dependent on estrogen for proliferation, the estrogen receptor is an important drug target for breast cancer
Three major sources of estrogen
(1) by direct secretion from the ovary in reproductive-age women
(2) by conversion of circulating androstenedione (A), originating from the adrenal or ovary or both, to estrone (E 1 ) in peripheral tissues
(3) by conversion of A to E 1 in estrogen target tissues.
Relative strength of estrogens
E2 >> E1
The expression of genes that encode the enzymes ____ and reductive ____ is critical for E2 formation from E1.
The expression of genes that encode the enzymes aromatase and reductive 17β-hydroxysteroid dehydrogenases (17β-HSD) is critical for E2 formation from E1.
Production of Estrogen figure
The classic hormones that use nuclear receptors for signaling are ___ and ___.
The classic hormones that use nuclear receptors for signaling are thyroid hormone and steroid hormones
In addition to hormones, nuclear receptors also mediate the biologic effects of some ___.
In addition to hormones, nuclear receptors also mediate the biologic effects of some vitamins.
Specifically, vitamins D and A.
Nuclear receptor signaling
Much of the regulation of nuclear receptor signaling is mediated by interactions of nuclear receptors with ____.
Much of the regulation of nuclear receptor signaling is mediated by interactions of nuclear receptors with coregulators (costimulators and corepressors).
Major domains of nuclear receptors
DNA-binding domain: Controls gene-specificity of the receptor
Ligand-binding domain: Activates the transcriptional effects. Operates by recruitment of coactivators or corepressors. May operate geneteically or epigenetically.
Dynamic range of transcriptional effects of nuclear receptors
SERM
Selective estrogen receptor modulator
such as tamoxifen
Receptor antagonists in some tissues like breast tissue and breast cancer cells, but act as agonists in other tissues such as endometrium and bone.
Breast anatomy
The most common type of breast cancer
ductal carcinoma
Breast cancer risk factors
- Personal history of breast cancer
- Family history of breast cancer
- Inherited mutations in BRCA1 or 2
- Personal history of non-canceorus breast disease
- Dense tissue finding on mammogram
- Several symtpoms which expose the breast to more estrogen:
- Early menstruation age
- Older age at first birth or never given birth
- Starting menopause later
- Taking hormones
- Radiation exposure
- Alcoholism
- Obesity
- Being white
Protective factors for breast cancer
- Estrogen-only hormone therapy after hysterectomy
- SERMs
- Aromatase inhibitors
- Exercise
Signs of breast cancer (or other conditions, not exclusive)
- A lump or thickening in or near the breast or in the underarm area.
- A change in the size or shape of the breast.
- A dimple or puckering in the skin of the breast
- A nipple turned inward into the breast.
- Fluid, other than breast milk, from the nipple, especially if it’s bloody.
- Scaly, red, or swollen skin on the breast, nipple, or areola (the dark area of skin around the nipple).
- Dimples in the breast that look like the skin of an orange, called peau d’orange.
Mammogram
Breast x-ray
Sonogram
Generated by ultrasound, a procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
Four types of biopsy used in breast cancer
Excisional biopsy: The removal of an entire lump of tissue.
Incisional biopsy: The removal of part of a lump or a sample of tissue
Core biopsy: The removal of tissue using a wide needle.
Fine-needle aspiration (FNA) biopsy: The removal of tissue or fluid, using a thin needle.
Estrogen and progesterone receptor test
A test to measure the amount of estrogen and progesterone (hormones) receptors in cancer tissue. If there are more estrogen and progesterone receptors than normal, the cancer is called estrogen and/or progesterone receptor positive. This type of breast cancer may grow more quickly.
The test results show whether treatment to block estrogen and progesterone may stop the cancer from growing.
Human epidermal growth factor type 2 receptor (HER2/neu) test
A laboratory test to measure how many HER2/neu genes there are and how much HER2/neu protein is made in a sample of tissue. If there are more HER2/neu genes or higher levels of HER2/neu protein than normal, the cancer is called HER2/neu positive.
This type of breast cancer may grow more quickly and is more likely to spread to other parts of the body. The cancer may be treated with drugs that target the HER2/neu protein, such as trastuzumab and pertuzumab.
Multigene tests
Tests in which samples of tissue are studied to look at the activity of many genes at the same time. These tests may help predict whether cancer will spread to other parts of the body or recur (come back). There are many types of multigene tests.
Examples: Oncotype DX (whether stage I or II ER+ cancer will spread), MammaPrint (whether any stage I or II breast cancer will spread)
Three types of breast cancer
Hormone Receptor + or Hormone Receptor - (either estrogen or progesterone)
HER2/neu+ or HER2/neu-
Triple negative (ER-, PR-, HER2/neu-)
Staging of breast cancer
- Lymph node biopsy
- Chest x-ray
- CAT scan
- Bone scan
- PET scan
CAT scan
A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly (contrast).
Bone scan
A procedure to check if there are cancer cells in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones and is detected by a scanner
PET scan
A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do
Ductal carcinoma in situ
A noninvasive condition in which abnormal cells are found in the lining of a breast duct. The abnormal cells have not spread outside the duct to other tissues in the breast. In some cases, DCIS may become invasive cancer and spread to other tissues. At this time, there is no way to know which lesions could become invasive
Lobular carcinoma in situ
A condition in which abnormal cells are found in the lobules of the breast. This condition seldom becomes invasive cancer
Paget disease of the nipple
A condition in which abnormal cells are found in the nipple only.
Inflammatory breast cancer
Cancer has spread to the skin of the breast and the breast looks red and swollen and feels warm. The redness and warmth occur because the cancer cells block the lymph vessels in the skin. The skin of the breast may also show the dimpled appearance called peau d’orange (like the skin of an orange). There may not be any lumps in the breast that can be felt. Inflammatory breast cancer may be stage IIIB, stage IIIC, or stage IV
peau d’orange
Breast-conserving surgery
An operation to remove the cancer and some normal tissue around it, but not the breast itself. Part of the chest wall lining may also be removed if the cancer is near it. This type of surgery may also be called lumpectomy, partial mastectomy, segmental mastectomy, quadrantectomy, or breast-sparing surgery
Modified radical mastectomy
Surgery to remove the whole breast that has cancer, many of the lymph nodes under the arm, the lining over the chest muscles, and sometimes, part of the chest wall muscles.
The Halstedian mastectomy
Preoperative therapy or neoadjuvant therapy
Chemotherapy may be given before surgery to remove the tumor. When given before surgery, chemotherapy will shrink the tumor and reduce the amount of tissue that needs to be removed during surgery.
Postoperative therapy or adjuvant therapy
Postoperative chemotherapy or radiation
External radiation therapy
uses a machine outside the body to send radiation toward the cancer
Internal radiation therapy
uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer.
Internal radiation therapy with ___ is used to relieve bone pain caused by breast cancer that has spread to the bones
Internal radiation therapy with strontium-89 is used to relieve bone pain caused by breast cancer that has spread to the bones.
Strontium89 is injected into a vein and travels to the surface of the bones. Radiation is released and kills cancer cells in the bones.
Hormone therapy
A cancer treatment that removes hormones or blocks their action and stops cancer cells from growing.
Ovarian ablation
Treatment to stop the ovaries from making estrogen
Hormone therapy with tamoxifen is often given to patients with. . .
early localized breast cancer that can be removed by surgery and those with metastatic breast cancer
Women taking tamoxifen should have ___.
Women taking tamoxifen should have a pelvic exam every year to look for any signs of cancer
Luteinizing hormone-releasing hormone therapy
Given to some premenopausal women who have just been diagnosed with hormone receptor positive breast cancer. LHRH agonists decrease the body’s estrogen and progesterone.
The two main options for postmenopausal women who have HR+ cancer are. . .
LHRH therapy
Aromatase inhibitor therapy
Targeted therapy
Type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells.
Monoclonal antibodies, tyrosine kinase inhibitors, cyclindependent kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and PARP inhibitors are types of targeted therapies used in the treatment of breast cancer.
Types of monoclonal antibody therapy for breast cancer
Trastuzumab (Herceptin): anti-HER2
Pertuzumab: anti-HER2
Ado-trastuzumab emtansine: anti-HER2 with attached chemotherapy
Lapatinib
Tyrosine kinase inhibitor that blocks the effects of the HER2 protein and other proteins inside tumor cells. It may be used with other drugs to treat patients with HER2 positive breast cancer that has progressed after treatment with trastuzumab
Palbociclib
Cyclin-dependent kinase inhibitor used with the drug letrozole to treat breast cancer that is estrogen receptor positive and HER2 negative and has spread to other parts of the body.
It is used in postmenopausal women whose cancer has not been treated with hormone therapy. Palbociclib may also be used with fulvestrant in women whose disease has gotten worse after treatment with hormone therapy
Everolimus
An mTOR inhibitor used in postmenopausal women with advanced hormone receptor positive breast cancer that is also HER2 negative and has not gotten better with other treatment.
Curative and Palliative chemotherapy chart
Cell-cycle specific chemotherapy
Chemotherapeutic agents that are effective only against replicating cells
___ chemotherapeutics tend to have more side effects in noncancerous cells.
Cell-cycle nonspecific chemotherapeutics tend to have more side effects in noncancerous cells.
Log kill
A log kill of x is a reduction in the total number of cells by a factor of 10x
For example, a 5 log kill results in a tumor burden of (10-5) x N, where N is the original number of tumor cells.
For most bacterial infections, a ___-log kill results in cure.
For most bacterial infections, a five-log kill results in cure.
Cancer is harder to cure.
Pharmacologic sanctuaries
Places where transport constraints prevent certain chemotherapeutic agents from entering
Cross-resistance
May follow the use of one type of antibiotic or chemotherapeutic agent.
For example, no penicillins are used on MRSA because methicillin is close enough to other penicillins that it is likely that resistance will develop.
P-glycoprotein
Stepwise selection of an amplified gene that codes for a transmembrane protein (P-glycoprotein for “permeability” glycoprotein) is responsible for multidrug resistance. This resistance is due to adenosine triphosphate–dependent pumping of drugs out of the cell in the presence of P-glycoprotein.
Filgrastim
Recombinant GM-CSF. May be given in combination with chemotherapy to delay neutropenia in the presence of chemotherapeutic agents.
The clinical symptoms of inflammatory breast cancer are the result of . . .
. . . spread of the tumor to lymphatic vessels in the overlying skin of the breast
Sentinel lymph node biopsy usually involves ____ at the site of the tumor.
Sentinel lymph node biopsy usually involves injection of a tracer at the site of the tumor.
Paclitaxel
A microtubule inhibitor that acts by disrupting the mitotic spindle during mitosis, and thus requires that cells be actively dividing to induce cell death.
ER+ breast cancer therapy of choice in premenpausal vs postmenopausal women
Premenopausal: Just tamoxifen
Postmenopausal: Start w/ anostrazole, switch to tamoxifen if necessary.
Aromatise inhibitors prevent. . .
. . . synthesis of estrogen from androgens (like testosterone) in peripheral tissues.
