Breast cancer is the most common type of cancer that occurs in women and is second only to lung cancer as the leading cause of women's cancer-related deaths. The proposed project will address a virtually unstudied feature of the disease: the left-side prevalence of breast tumors. The overall hypothesis is that the left and right mammary glands are differentially susceptible to tumor-initiation and/or progression. If correct, differential left-right (L-R) susceptibility may be particularly important during puberty, when the rapid growth and remodeling of the embryonically established, rudimentary ductal network renders the mammary glands highly vulnerable to genetic, hormonal, and other environmental perturbations that promote neoplasias. To test this hypothesis, three mouse models of neoplastic development will be used: estrogen treated mice, which model early menarche, a well documented primary risk factor for breast cancer;MMTV-cNeu transgenic mice, a classic and widely used model of breast carcinogenesis;and MMTV-Wnt1 transgenic mice, a premier model for breast cancer stem cell studies. Putative L-R differences in mammary gland development will be systematically investigated at the morphological, cellular, and molecular levels, ranging from whole mount morphometric measurements of ductal network formation through differential L-R gene expression profiles. Particular attention will be given to the nodal signaling pathway. Nodal is a TGF? family member that is a master regulator of embryonic L-R asymmetric patterning. De-regulated expression of nodal pathway components is associated with poor prognostic outcome in breast cancer patients, suggesting an additional role for this pathway in mammary gland carcinogenesis.
Specific Aim 1 will determine whether expression of nodal pathway components and ductal patterning differ in the left versus right mammary glands of mice induced to undergo early menarche via estrogen exposure. Time -course studies encompassing pubescent development will quantify gene expression profiles and measure putative differences in the epithelial stem/progenitor cell pool, ductal epithelial cell growth, survival, and branching morphogenesis.
In Specific Aim 2, parallel studies will be performed in pubescent MMTV-cNeu and MMTV-Wnt1 transgenic mice to determine whether morphological and molecular L-R differences in mammary gland development arise and/or become accentuated early in oncogenesis. Because L-R bias for tumor formation also occurs for cancers in other bilaterally paired organs, and because there is emerging evidence that the 5-year survival rates for some cancers significantly differ according to the left versus right side of tumor formation, the significance of the proposed project is that investigation of breast cancer laterality ultimately may lead to improvements in the treatment and survival of breast cancer patients.
The proposed project will address a poorly understood aspect of breast cancer-the question of why more tumors develop in the left breast than the right. Experimentation will focus on genes and cellular processes that function during pubescent development and that may predispose left-side prevalence for tumor formation. The long-term significance of this study is that it may yield information on normal and neoplastic mammary gland development that could be used to improve delivery of current therapies or development of new treatment regimes.
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|Levin, Michael; Klar, Amar J S; Ramsdell, Ann F (2016) Introduction to provocative questions in left-right asymmetry. Philos Trans R Soc Lond B Biol Sci 371:|
|Robichaux, J P; Hallett, R M; Fuseler, J W et al. (2015) Mammary glands exhibit molecular laterality and undergo left-right asymmetric ductal epithelial growth in MMTV-cNeu mice. Oncogene 34:2003-10|
|Fuseler, John W; Robichaux, Jacqulyne P; Atiyah, Huda I et al. (2014) Morphometric and fractal dimension analysis identifies early neoplastic changes in mammary epithelium of MMTV-cNeu mice. Anticancer Res 34:1171-7|
|Veltmaat, Jacqueline M; Ramsdell, Ann F; Sterneck, Esta (2013) Positional variations in mammary gland development and cancer. J Mammary Gland Biol Neoplasia 18:179-88|