Currently, targeted agents are in clinical testing for treatment of ER- breast cancer, but have not been adequately tested for prevention. This is because, without a better understanding of the biology of human breast cancer initiation, Phase I/II testing of targeted agents for preventing ER- breast cancer will be too risky and expensive. To meet these challenges, we aim to identify key signaling networks activated during initiation of ER- breast cancer in women in our high-risk cohort and use these networks to target prevention. Normal mammary gland homeostasis requires the coordinated regulation of signaling networks. Currently we lack an understanding of 1) whether the signaling networks that are activated in aggressive ER- breast cancer are also activated in mammary atypia, and 2) if so, whether activation of specific signaling networks predicts cancer initiation and progression. Here we will investigate whether signaling network activation in atypia predicts subsequent cancer etiology. Activation of Akt/mTOR, IL6/Stat3, EGRF/MEK/ERK, and mitochondrial survival pathways are known to predict aggressive biology in ER- breast cancer. Our Preliminary Data provide evidence that activation of these poor-prognosis signaling networks can be detected in mammary atypia from high risk women. However, just because we can identify signatures with high inter-class coefficients of variation between subjects, does not necessarily imply those processes are important for cancer etiology. Here will test the hypothesis that signaling pathways that underlie the aggressive behavior of ER- breast cancer can be detected in mammary atypia from high-risk women, and whether these signaling pathways can be used to predict cancer initiation and guide targeted prevention strategies.
Aim 1 will test whether phosphoprotein signatures identified in ER- breast cancers are present in premalignant lesions in high-high risk women.
Aim 2 will prospectively investigate whether phosphoprotein signatures predict initiation of ER- breast cancer.
Aim 3 will investigate whether RPPM signatures predict in vitro sensitivity to targeted agents.
Aim 4 will perform Pilot Testing and use phosphoprotein signatures to select and track response to targeted agents to prevent breast cancer in high-risk women with mammary atypia. Significance: Here we will identify protein signaling pathways that are activated during breast cancer initiation. Information gained in this proposal will allow us to identify activated signaling pathways in atypia, test whether pathway activation predicts cancer etiology, and use this information to select, and track response to, targeted agents.
Currently, targeted agents are in clinical testing for treatment of ER- breast cancer, but have not been adequately tested for prevention. Here we will identify protein signaling pathways that are activated during breast cancer initiation and test in live patient cells whether proteomic signatures correctly identify sensitivity to targeted agents. The strategies we develop will allow us to identify activated signaling pathways in atypia, test whether pathway activation predicts cancer etiology, and use this information to select and track response to targeted agents.
|Dietze, Eric C; Chavez, Tanya A; Seewaldt, Victoria L (2018) Obesity and Triple-Negative Breast Cancer: Disparities, Controversies, and Biology. Am J Pathol 188:280-290|
|Glass, Oliver K; Bowie, Michelle; Fuller, Julie et al. (2017) Differential response to exercise in claudin-low breast cancer. Oncotarget 8:100989-101004|
|Wang, Xiao; Yao, Jun; Wang, Jinyang et al. (2017) Targeting Aberrant p70S6K Activation for Estrogen Receptor-Negative Breast Cancer Prevention. Cancer Prev Res (Phila) 10:641-650|
|Bowie, Michelle; Pilie, Patrick; Wulfkuhle, Julia et al. (2015) Fluoxetine induces cytotoxic endoplasmic reticulum stress and autophagy in triple negative breast cancer. World J Clin Oncol 6:299-311|
|Tung, Jason C; Barnes, J Matthew; Desai, Shraddha R et al. (2015) Tumor mechanics and metabolic dysfunction. Free Radic Biol Med 79:269-80|
|Dietze, Eric C; Sistrunk, Christopher; Miranda-Carboni, Gustavo et al. (2015) Triple-negative breast cancer in African-American women: disparities versus biology. Nat Rev Cancer 15:248-54|
|Ibarra-Drendall, Catherine; Troch, Michelle M; Barry, William T et al. (2012) Pilot and feasibility study: prospective proteomic profiling of mammary epithelial cells from high-risk women provides evidence of activation of pro-survival pathways. Breast Cancer Res Treat 132:487-98|
|Seewaldt, Victoria L (2012) Cancer: Destiny from density. Nature 490:490-1|
|D'Amato, Nicholas C; Ostrander, Julie H; Bowie, Michelle L et al. (2012) Evidence for phenotypic plasticity in aggressive triple-negative breast cancer: human biology is recapitulated by a novel model system. PLoS One 7:e45684|
|Henderson, Brian E; Lee, Norman H; Seewaldt, Victoria et al. (2012) The influence of race and ethnicity on the biology of cancer. Nat Rev Cancer 12:648-53|
Showing the most recent 10 out of 11 publications