1. Breast Cancer Mechanisms 1

2. 2 Her2

3. 3

4. 4

5. 5

6. 6

7. 7

8. 8

9. 9

10. 10 10-100x

11. 11

12. 12 AKT

13. 13 Small Molecule Kinase Inhibitors

14. 14

15. 15

16. 16 PI3K minutes after inhibition of Her2

17. 17

18. 18 Monoclonal Antibodies

19. 19

20. 20

21. 21 “Humanized” monoclonal antibody

22. 22 Herceptin™

23. 23

24. 24

25. 25

26. 26 Estrogen Receptor

27. 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. 28 Estradiol (17β-estradiol)

29. 29

30. 30 estrogen receptor

31. 31

32. 32 estrogen receptor MAPK

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

34. 34 CytoplasmNucleus

35. 35 Selective Estrogen Receptor Modulators (SERMs)

36. 36 CYP2D6 CH 3 tamoxifen 4-hydroxy tamoxifen

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

38. 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. 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. 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. 41 Aromatase Inhibitors/Inactivators

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

43. 43 Mutant BRCAs