Daisy D' De Len, PhD

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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

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• 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.

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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.
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• 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.

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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

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Model of Breast Cancer Carcinogenesis
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Is IGF-II associated with the increased mortality
rate observed among African American women?
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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?????

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Nat Rev Cancer. 2004 Jul4(7)505-18
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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 !!
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• 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

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Insulin-like growth factor II - IGF-II
IGF-independent anti-proliferative
and pro-apoptotic signals
Targets IGF2 for degradation
Mitogenic and anti-apoptotic signals
Mitogenic signal (IGF2) Metabolic signal (insulin)
Adapted from LeRoith and Roberts (2003) Cancer
Letters 195127.
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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
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GH Growth Hormone

• Glycoprotein
• 191 A.A.
• Muscle Bone growth
• Metabolic regulation

Giantism and Dwarfism affect growing human
(young)
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Figure 45.14 Stress and the adrenal gland
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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.

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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

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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
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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