Jo Anne Zujewski, MDJo Anne Zujewski, MDCancer Therapy Evaluation ProgramCancer Therapy Evaluation Program

Division of Cancer Diagnosis and TreatmentDivision of Cancer Diagnosis and TreatmentNational Cancer InstituteNational Cancer Institute

May 2011May 2011

Breast Cancer Biology

Breast Cancer Theory: Halsted

• Operative breast cancer is a local-regional disease• The positive lymph node is the source of distant

metastases

Breast Cancer Theory: Systemic

• Operative breast cancer is a systemic disease• Positive lymph node is an indicator of host-tumor

relationship that permits metastases

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

Seminal observations that have Seminal observations that have led to the current understanding led to the current understanding

of breast cancer as a family of of breast cancer as a family of related diseases, not a single related diseases, not a single

monolithic process.”monolithic process.”

Molecular Portrait of Breast Cancers

HER-2Basal-like Luminal ALuminal B“Normal”

Sorlie T et al, PNAS 2001Slide courtesy of L. Carey

Subtypes and Prognosis

Sorlie T et al, PNAS 2001

Genetic FactorsGenetic 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

Hormones Growth factors Small interfering RNAs Post-translational modifications

methylation protein ubiquination phosphorylation

Epigenetic Factors

Breast Cancer

a multi-step process

genetic changes

epigenetic changes

mutagenic/nonmutagenic

risk factors

gene signatures

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.

Breast Cancer Development, Growth, Survival Breast Cancer Development, Growth, Survival and Metastasis Involves Multiple Interrelated and Metastasis Involves Multiple Interrelated

Pathways Pathways

Concurrent Concurrent targeting of targeting of

multiple multiple pathways pathways

will likely be will likely be optimal!!optimal!!