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    Research Grants Awarded

    Breastfeeding History And Undifferentiated Breast Cancer

    Study Section:
    RISK and Prevention, Epidemiology

    Scientific Abstract:
    Background: Relative risk of breast cancer decreases proportional to a woman’s lifetime duration of breastfeeding (30% risk reduction by 6 years), although Western women usually breastfeed a child for only a few months, if at all. High expression of the pi subunit of gamma aminobutyric acid type A receptors (GABApi) defines undifferentiated breast cancers that lack estrogen receptors and Her-2/neu (ER-/HER2-), have basal-like gene expression profile, and coexpress other genes associated with progenitor cells. In multivariate analysis, GABApi gene expression was also associated with younger age (p=0.0003) and shorter (<=6 months) lifetime duration of breastfeeding women (p=0.017, n=138). Breast cancer with high GABAp expression was more common in parous women who breastfed <3 months per child (26% versus 5%, p=0.004). Hypothesis: Retained progenitor cells after early cessation of breastfeeding are at risk for development of undifferentiated breast cancer that could be prevented by strategies to continue cellular differentiation after lactation ceases. Specific Aims: In aim 1 we define the association between breastfeeding duration and undifferentiated breast cancer defined by a genomic biomarker (GABApi). In aim 2 we explore strategies to induce differentiation in breast cancer cells that highly express GABApi. Study Design: We will compare GABApi gene expression in breast cancer samples with the duration of breastfeeding per child in 540 women to define with 99.9% statistical power whether undifferentiated breast cancer is associated with shorter breastfeeding, and to identify a threshold of breastfeeding duration beyond which women reduce their risk of future undifferentiated breast cancer. We will study the effects of allopregnanolone (a progesterone metabolite that downregulates GABApi) and folic acid (folic acid receptor gene is highly expressed with GABApi) on cellular differentiation, survival and proliferation in vitro . Potential Outcomes and Benefits: Definition of the association with duration of breastfeeding (aim 1) will support advisory guidelines for breastfeeding practice to reduce the risk of undifferentiated breast cancer for which other prevention strategies are lacking. Our laboratory studies (aim 2) will provide preclinical results to define future strategies for differentiation of progenitor cells that will prevent undifferentiated breast cancer in women who do not breastfeed.

    Lay Abstract:
    Background: A woman’s risk of future breast cancer is markedly reduced by prolonged lifetime duration of breastfeeding . However, many women living in developed nations can realistically breastfeed for only a few months per child, if at all. Our preliminary studies indicate that just a few months of breastfeeding per child might prevent the development of a specific type of breast cancer that lacks estrogen receptors and Her-2/neu (ER-/HER2-), has a distinct basal-like gene expression profile, and expresses high levels of genes associated with undifferentiated progenitor cells, including a specific genomic biomarker (GABApi). This type of breast cancer is difficult to prevent and difficult to treat when it develops. Hypothesis: If breastfeeding is stopped early, then normal differentiation of immature progenitor cells is stopped. Those surviving progenitor cells are at greater risk for development into breast cancer that is undifferentiated. Specific Aims: In aim 1 we determine whether there is a robust association between history of short breastfeeding duration and this undifferentiated type of breast cancer, as defined by increased levels of the biomarker (GABApi). In aim 2 we explore strategies to induce differentiation in breast cancer cells that highly express GABApi. Study Design: We will compare GABAp gene expression in breast cancer samples with the duration of breastfeeding per child in 540 women to obtain conclusive statistical proof of this association, and to then identify a threshold of breastfeeding duration that is a reasonable target for women who wish to reduce their risk of developing undifferentiated breast cancer. We will study the effects of two natural products (allopregnanolone and folic acid) on cellular differentiation, survival and proliferation in the laboratory. Potential Outcomes and Benefits: Definition of the association with duration of breastfeeding (aim 1) will support advisory guidelines for breastfeeding practice to prevent undifferentiated breast cancer. Our laboratory studies (aim 2) will provide preclinical results to define future strategies for differentiation of progenitor cells that will prevent undifferentiated breast cancer in women who do not breastfeed.