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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. Breast Cancer and African American Women

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daisy d de le n phd breast cancer laboratory center for health disparities and molecular medicine

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

slide2

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.
cancer death rates by race and ethnicity 1997 2001
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.

slide6

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.
slide7

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
slide9

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

slide10

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?????
slide12

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 !!

slide13

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
slide14

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.

slide15

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

gh growth hormone
Glycoprotein

191 A.A.

Muscle & Bone growth

Metabolic regulation

DWARFISH

GIGANTISM

GH – Growth Hormone

Giantism and Dwarfism affect growing

human (young)

slide25

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.
slide26

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
slide27

“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

slide28

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