The primary cilium is a membrane-enclosed organelle that projects from the surface of the cell and acts as the cell's antennae to communicate with its environment. The primary cillum senses signals from the environment and transduces receptor-mediated signaling events that control fundamental processes of developmental abnormalities and genetic diseases. I have demonstrated that the majority of primary cilia found in the murine and human mammary glands are expressed on the surface of myoepithelial cells. Nothing is known about the function of the cilium in the environment. Cilia projecting from the surface of myoepithelial ceils are Ideally positioned to play a sensory role to regulate stromal-epithelial as well as myoepithelial-luminal epithelial interactions. Communication between the microenvironment plays a critical role in the expansion and function of the mammary ductal tree during development, pregnancy, lactation and involution. I hypothesize that cilia mediate stromal-epithelial and myoepithelial-luminal epithelial communications to regulate mammary gland development, pregnancy and lactation.
The specific aims described in this application are designed to characterize the pattem of expression of primary cilia and determine the function of primary cilia in normal mammary gland development, pregnancy, lactation and involution. I will analyze the mammary glands from murine models of ciliary dysfunction to determine whether ductal invasion, branching morphogenesis, tissue architecture, lobular-alveolar differentiation, lactation and involution are abrogated by loss of functional cilia. Preliminary data indicate that ductal invasion, branching morphogenesis, lobular-alveolar differentiation and lactation are decreased in the absence of functional cilia. Preliminary data also suggests that canonical Wnt signaling is increased and noncanonical Wnt signaling is decreased In the absence of functional cilia. These exciting results suggest that the primary cilium is involved in regulating Wnt signaling during mammary gland development. Given that cilia appear to control processes important in mammary gland development and breast cancer, such as ductal invasion, branching morphogenesis and differentiation, developing a better understanding of the mechanisms by which cilia function may provide important insight into the etiology and progression of breast cancer. I also believe studying primary cilia in the mammary gland will uncover ciliary functions that will contribute to a better understanding of the many genetic diseases caused by ciliary dysfunction.

Public Health Relevance

Given that cilia appear to control processes important in mammary gland development and breast cancer, such as ductal invasion, branching morphogenesis and differentiation, developing a better understanding of the mechanisms by which cilia function may provide important insight into the etiology and progression of breast cancer. I also believe studying primary cilia in the mammary gland will uncover ciliary functions that will contribute to a better understanding of the many genetic diseases caused by ciliary dysfunction.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Transition Award (R00)
Project #
5R00HD056965-05
Application #
8130629
Study Section
Special Emphasis Panel (NSS)
Program Officer
Raiten, Daniel J
Project Start
2007-09-15
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$246,510
Indirect Cost
Name
University of Arizona
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Hassounah, Nadia B; Nagle, Ray; Saboda, Kathylynn et al. (2013) Primary cilia are lost in preinvasive and invasive prostate cancer. PLoS One 8:e68521
Hassounah, Nadia B; Bunch, Thomas A; McDermott, Kimberly M (2012) Molecular pathways: the role of primary cilia in cancer progression and therapeutics with a focus on Hedgehog signaling. Clin Cancer Res 18:2429-35
McDermott, Kimberly M; Liu, Bob Y; Tlsty, Thea D et al. (2010) Primary cilia regulate branching morphogenesis during mammary gland development. Curr Biol 20:731-7