Breast Cancer Mechanisms 1

2 Her2

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x

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12 AKT

13 Small Molecule Kinase Inhibitors

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16 PI3K minutes after inhibition of Her2

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18 Monoclonal Antibodies

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21 “Humanized” monoclonal antibody

22 Herceptin™

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24

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26 Estrogen Receptor

27 Estrogen Receptor Expression in normal breast tissue is low  none  Expression can increase (5% of cells to 26% of cells in one study) in breast cancer  Levels of circulating estrogen can also be increased (up 15% in one study) in some women diagnosed with breast cancer

28 Estradiol (17β-estradiol)

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30 estrogen receptor

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32 estrogen receptor MAPK

33 estrogen receptor estrogen G C co-repressor In breast cells In other cells

34 CytoplasmNucleus

35 Selective Estrogen Receptor Modulators (SERMs)

36 CYP2D6 CH 3 tamoxifen 4-hydroxy tamoxifen

37 Potential benefits of Tamoxifen: Decreased growth/division of breast cancer cells Lowered blood cholesterol Increase in bone density (decrease osteoporosis/fracture)

38 Potential side effects of Tamoxifen: Early onset of menopause Menopausal symptoms (hot flashes, vaginal dryness/itching, irregular menstrual periods) Headache, nausea, vomiting Skin rash Fatigue Fluid retention and/or weight gain Altered fertility

39 Potential side effects of Tamoxifen (continued): Increase risk of blood clots Increased risk of stroke Increased risk of developing cataracts Increased risk of endometrial cancer SERMs will not work on Estrogen-receptor-negative breast cancers.

40 Other SERMs: Raloxifene —used to reduce the risk of hormone-receptor-positive breast cancer in post- menopausal women who haven't been diagnosed but are at higher-than-average risk for disease. Raloxifene is also used to treat/prevent osteoporosis in post-menopausal women. Note, Raloxifene is not used to treat breast cancer after it's been diagnosed. Toremifene —used to treat post-menopausal women diagnosed with advanced (metastatic) hormone-receptor-positive breast cancer. FDA approved, but not used frequently in the U.S.

41 Aromatase Inhibitors/Inactivators

42 Anastrozole Letrozole Exemestane Used to treat Estrogen-receptor positive breast cancer in post-menopausal women

43 Mutant BRCAs