Triple-Negative Breast Cancers (TNBC = negative on clinical assays for ER, PR and HER2) are among the most clinically challenging because of their inherent aggressive biology and lack of treatment options (typically limited to chemotherapy only). These tumors are also more common in young African American women, thus contributing to racial disparities and mortality. To advance our knowledge of the biology of TNBC, we believe it critical to precisely define the biological entities that are present within this known heterogeneous group, to next determine their driving biology, and to lastly employ robust biomarkers for defining more homogeneous subgroups of TNBC for pairing with the appropriate targeted drug(s). We hypothesize that TNBC are composed of two main biologically distinct groups (i.e. Basal-like and Claudin-low subtypes), and that the best way to make therapeutic advances is to comprehensively study these subtypes to identify their unique and potentially targetable molecular features. We hypothesize that a high proportion of Basal-like breast cancers have evidence of a DNA repair deficiency caused by either loss of BRCA1/2, or loss of chromosome 5q, which contains many genes crucial to DNA repair (RAD17, RAD50, UIMC1). Conversely, Claudin-low tumors do not share these defects, but have unique properties including an active immune infiltrate and evidence of epithelial-to-mesenchymal transition. We will test the hypothesis that DNA repair defects, and differences in growth factor signaling pathways, can be used to therapeutically target TNBC by 1) using multiple validated pre-clinical murine models and primary human tumor xenografts, and testing promising new targeted agents (PARP inhibitors, PIKSCA inhibitors and MEK inhibitors), 2) combinations of these agents, and combinations with DNA-damaging chemotherapuetics (carboplatin), and 3) by studying tumor samples from 4 randomized neoadjuvant clinical trials testing carboplatin and/or ABT- 888 in TNBC patients with the hypothesis that these DNA damage-inducing agents will be particularly effective on tumors that have a profound DNA repair defect. We will perform gene expression profiling and DNA copy number analyses to test pre-defined genomic signatures and copy number changes as markers of responsiveness, and for de novo profile discovery. Our across-species comparative biology approach merges pre-clinical models with human clinical trials, and if successful, we will identify new targeted agents for TNBC along with companion diagnostics.
Breast cancer is the second most common cause of cancer deaths in women in the US each year, with Triple Negative Breast Cancers being overrepresented within these deaths and are among the most clinically challenging because of their paucity of treatment options. Therefore, it is imperative to understand the driving biology of TNBC, and then to target this with the right drugs so that improved outcomes can be achieved.
|Mobley, Robert J; Raghu, Deepthi; Duke, Lauren D et al. (2017) MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition. Cell Rep 18:2387-2400|
|Kohler, Racquel E; Gopal, Satish; Miller, Anna R et al. (2017) A framework for improving early detection of breast cancer in sub-Saharan Africa: A qualitative study of help-seeking behaviors among Malawian women. Patient Educ Couns 100:167-173|
|Valle, Carmina G; Deal, Allison M; Tate, Deborah F (2017) Preventing weight gain in African American breast cancer survivors using smart scales and activity trackers: a randomized controlled pilot study. J Cancer Surviv 11:133-148|
|Sharma, Priyanka; López-Tarruella, Sara; García-Saenz, Jose Angel et al. (2017) Efficacy of Neoadjuvant Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohorts. Clin Cancer Res 23:649-657|
|Mullooly, Maeve; Yang, Hannah P; Falk, Roni T et al. (2017) Relationship between crown-like structures and sex-steroid hormones in breast adipose tissue and serum among postmenopausal breast cancer patients. Breast Cancer Res 19:8|
|Hoffman, Joshua D; Graff, Rebecca E; Emami, Nima C et al. (2017) Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk. PLoS Genet 13:e1006690|
|Visvanathan, Kala; Fackler, MaryJo S; Zhang, Zhe et al. (2017) Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study. J Clin Oncol 35:751-758|
|Zawistowski, Jon S; Bevill, Samantha M; Goulet, Daniel R et al. (2017) Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex. Cancer Discov 7:302-321|
|Bowerman, Charles J; Byrne, James D; Chu, Kevin S et al. (2017) Docetaxel-Loaded PLGA Nanoparticles Improve Efficacy in Taxane-Resistant Triple-Negative Breast Cancer. Nano Lett 17:242-248|
|Heng, Yujing J; Lester, Susan C; Tse, Gary Mk et al. (2017) The molecular basis of breast cancer pathological phenotypes. J Pathol 241:375-391|
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