1. Jo Anne Zujewski, MD Cancer Therapy Evaluation Program Division of Cancer Diagnosis and Treatment National Cancer Institute May 2011 Breast Cancer Biology

2. Breast Cancer Theory: Halsted Operative breast cancer is a local-regional disease The positive lymph node is the source of distant metastases

3. Breast Cancer Theory : Systemic Operative breast cancer is a systemic disease Positive lymph node is an indicator of host-tumor relationship that permits metastases

4. Breast Cancer Theory: Spectrum Operative breast cancer is a systemic disease in many but not all cases Positive lymph node is correlated with the subsequent appearance of distant metastases

5. Seminal observations that have led to the current understanding of breast cancer as a family of related diseases, not a single monolithic process.”

6. Molecular Portrait of Breast Cancers HER-2 Basal-like Luminal A Luminal B“Normal” Sorlie T et al, PNAS 2001 Slide courtesy of L. Carey

7. Subtypes and Prognosis Sorlie T et al, PNAS 2001

8. Genetic Factors  Oncogenes  Tumor suppressor genes  DNA repair genes  Carcinogen activating/deactivating genes  Cell cycle genes  Cell cycle checkpoint genes  Cell death genes  Cell signaling genes  Cellular senescence genes  Cellular differentiation genes  Metastasis/invasion genes

9.   Hormones  Growth factors  Small interfering RNAs  Post-translational modifications  methylation  protein ubiquination  phosphorylation Epigenetic Factors

10. Breast Cancer    a multi-step process  genetic changes  epigenetic changes  mutagenic/nonmutagenic risk factors  gene signatures

11. In pathways, messages are sent from the outside of the cell to the inside of the cell through messengers. SIGNAL TRANSDUCTION Cells respond to external signals through pathways.

12. Breast Cancer Development, Growth, Survival and Metastasis Involves Multiple Interrelated Pathways Concurrent targeting of multiple pathways will likely be optimal!!