Daisy D. De León, PhD Breast Cancer Laboratory Center for Health Disparities and Molecular Medicine

1. Uncovering Biological Determinants Modulating Breast Cancer Aggressiveness in African American Women Daisy D. De León, PhD Breast Cancer Laboratory Center for Health Disparities and Molecular Medicine

2. Breast Cancer and African American Women • Breast cancer is the most feared malignancy among American women. • Although Caucasian women develop breast cancer at higher rates than African American (AA) women do, African American women have a higher mortality rate. • According to a National Cancer Institute study, AA women were 2.2 times more likely to die from breast cancer than their C counterparts. • An estimated 19,010 African American women were expected to be diagnosed with breast cancer in 2007. • An estimated 5830 African American women were expected to die of breast cancer in 2007.

3. Cancer Death Rates*, by Race and Ethnicity, 1997-2001 *Per 100,000, age-adjusted to the 2000 US standard population. † Hispanic is not mutually exclusive from whites, African Americans, Asian/Pacific Islanders, and American Indians. Source: Surveillance, Epidemiology, and End Results Program, 1975-2001, Division of Cancer Control and Population Sciences, National Cancer Institute, 2004.

6. Breast Cancer and African American Women • The poorer outcomes with regard to breast cancer in AA women have been historically attributed to the more advanced stage of disease at the time of presentation for medical attention. • This, however, does not totally explain the survival differences. After taking into account socioeconomic status, health care access and educational status, a study showed that survival among AA women remained significantly lower. • Genetic/biological factors that contribute to the risk of developing breast cancer and the poorer outcomes of African American women with the disease are not completely understood.

7. Breast Cancer and African American Women • Known differences in Biological Factors -What do they mean? • AA women have increased: • “Mutant p53” = decreased survival • Levels of cathepsin-D = increased metastasis • Number of estrogen receptor negative tumors • “Triple negative tumors” • Resistant tumors = do not respond to chemotherapy

8. Model of Breast Cancer Carcinogenesis

9. Is IGF-II associated with the increased mortality rate observed among African American women?

10. IGF-II • IGF-II is secreted by most tumors including breast cancer. • IGF-II stimulates cell growth, metastasis, chemoresistance • IGF-II increase in mice develops breast cancer tumors at a higher frequency than mice with low IGF-II • IGF-II in Humans?????

11. Nat Rev Cancer. 2004 Jul;4(7):505-18

12. Breast Cancer and African American Women • Known differences in Biological Factors - What do they mean? • AA women have increased: • “Mutant p53” = decreased survival • Levels of cathepsin-D = increased metastasis • Number of estrogen receptor negative tumors • “Triple negative tumors” • Resistant tumors = do not respond to chemotherapy All of these characteristics are associated with IGF-II !!

13. What regulates IGF-II levels? What is its function? • Nutrition - to regulate energy • Radiation - to protect skin • Fat intake - to regulate metabolism • Sugar intake - to regulate energy • Hormones - Estrogen, progesterone, prolactin • STRESS

14. Insulin-like growth factor II - IGF-II IGF-independent anti-proliferative and pro-apoptotic signals Targets IGF2 for degradation Mitogenic signal (IGF2) Metabolic signal (insulin) Mitogenic and anti-apoptotic signals Adapted from: LeRoith and Roberts (2003) Cancer Letters 195:127.

15. Research Project Hypothesis: IGF-II levels are higher among African American women with breast cancer as compared to Caucasian women. Thus, IGF-II promotes a more aggressive disease that contributes to the increased mortality observed in this ethnic group. Design: Analysis of IGF-II and IGF-II related proteins in paired normal/tumor tissues from AA & C breast cancer patients. A similar analysis was performed in breast cancer cells obtained from AA & C patients. Materials: BC tissue samples were obtained from the “NCI” supported *Cooperative Human Tissue Network. Cell lines were obtained from ATCC. IRB approved and funded by a grant from the National Center for Minority Health & Health Disparities

21. Glycoprotein 191 A.A. Muscle & Bone growth Metabolic regulation DWARFISH GIGANTISM GH – Growth Hormone Giantism and Dwarfism affect growing human (young)

24. Figure 45.14 Stress and the adrenal gland

25. Conclusions • IGF-II is highly expressed in normal and tumor tissues of AA women. • IGF-II related proteins are also highly expressed in normal and tumor tissues of AA women. • IGF-II levels in tumor cells established from of AA women are also expressed at high levels, stimulating rapid growth and promoting chemoresistance.

26. What Now???? • Expand analysis to a larger sample - Establish a collaboration with Drew University to analyze 3,200 breast cancer paired samples and blood from AA women. • Clinical trial to analyze levels of cathepsin D and IGF-II in AA and C women treated with Resveratrol - chemoprevention • Develop a clinical assay to assess IGF-II levels to follow up BC patients recurrence

27. “I am myself and my circumstance, and if I do not save it, I do not save myself.”José Ortega y Gasset, (1883-1955), Spanish writer, philosopher and revolutionary

28. Acknowledgments • Peter Nissley, MD (NCI) • Tian Jian, MD,PhD • Sharda Vyas, MD,PhD • Marino De Leon, PhD • Frankis Almaguel • Nathan Wall, PhD Funded by The National Center for Minority Health and Health Disparities