The ErbB family of receptor tyrosine kinases includes EGFR, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4. Abundant evidence supports the causal role of HER2 overexpression in up to 25% of all breast cancers. While HER3 lacks intrinsic kinase activity, HER3 is often over-expressed in breast cancers that overexpress HER2. Heterodimerization of HER2 with HER3 increases proliferation, survival, and transformation of breast cells. Tyrosine-phosphorylated HER3 potently engages the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, which increases tumor cell proliferation and survival. Inhibitors of HER2 such as the monoclonal antibody trastuzumab and the dual EGFR/HER2 tyrosine kinase inhibitor (TKI) lapatinib are currently approved for treatment of HER2-overexpressing metastatic breast cancer. However, many breast cancers with HER2 gene amplification do not respond and/or eventually escape trastuzumab and lapatinib. It is our hypothesis that 1) signaling by HER2:HER3 heterodimers is essential for mammary tumorigenesis, and 2) HER3 expression enhances tumor cell survival, rendering tumors resistant to therapies that target HER2. According to these hypotheses, HER2-positive breast tumors would be less frequent and less malignant in the absence of HER3, and therapeutic antibodies targeting HER3 may prevent or reverse trastuzumab or lapatinib resistance. These results would support the development of treatments targeting HER3 and its downstream effectors as alternative or adjuvant therapy for patients with HER2-positive breast cancers. We have designed experiments testing this hypothesis, using a novel genetic approach to conditionally eliminate ErbB3 (endogenous mouse HER3) expression specifically in the mammary epithelial cells (MECs) of mice.
In Aim 1, we will determine if HER3/ErbB3 is required for development of the mammary epithelium. We will use mice harboring MEC-specific loss of ErbB3 to examine mammary glands at each stage of post-natal mammary gland development. These studies will reveal the role of HER3/ErbB3 in untransformed MECs that may ultimately contribute to transformation. Experiments in Aim 2 will determine if HER3/ErbB3 is required for mammary tumorigenesis in vivo. We will use genetically engineered mouse models of HER2-driven and HER2-independent breast cancers to determine if ErbB3 is required for their formation and malignant progression.
Aim 3 will determine if HER3 inhibition (genetic and pharmacologically) sensitizes HER2 overexpressing breast cancer cells to anti-HER2 therapies. Mice bearing HER2-overexpressing breast cancers will be treated with monoclonal antibodies targeting HER3 in combination with lapatinib and trastuzumab. In summary, the experiments outlined in this proposal will provide the necessary knowledge with which to determine if selective targeting of ErbB3 might be an alternative choice for advanced therapy tailored to HER2-overexpressing breast cancers, as well as those that do not overexpress HER2.

Public Health Relevance

These studies will provide a mechanistic understanding of how ErbB3 signaling influences complex biological events during mammary gland development and tumorigenesis. Experiments will determine if selective targeting of ErbB3 might be an alternative choice for advanced therapy tailored to HER2-overexpressing breast cancers, as well as those that do not overexpress HER2.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA143126-03
Application #
8196980
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Forry, Suzanne L
Project Start
2009-12-09
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$313,989
Indirect Cost
$112,714
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Stanford, Jamie C; Young, Christian; Hicks, Donna et al. (2014) Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J Clin Invest 124:4737-52
Balko, Justin M; Schwarz, Luis J; Bhola, Neil E et al. (2013) Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer. Cancer Res 73:6346-58
Bhola, Neil E; Balko, Justin M; Dugger, Teresa C et al. (2013) TGF-* inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest 123:1348-58
Hanker, Ariella B; Pfefferle, Adam D; Balko, Justin M et al. (2013) Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. Proc Natl Acad Sci U S A 110:14372-7
Morrison, Meghan M; Hutchinson, Katherine; Williams, Michelle M et al. (2013) ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. J Clin Invest 123:4329-43
Cook, Rebecca S; Jacobsen, Kristen M; Wofford, Anne M et al. (2013) MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis. J Clin Invest 123:3231-42
Balko, Justin M; Miller, Todd W; Morrison, Meghan M et al. (2012) The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium. Proc Natl Acad Sci U S A 109:221-6
Vaught, David B; Stanford, Jamie C; Young, Christian et al. (2012) HER3 is required for HER2-induced preneoplastic changes to the breast epithelium and tumor formation. Cancer Res 72:2672-82
Cook, Rebecca S; Garrett, Joan T; Sanchez, Violeta et al. (2011) ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis. Cancer Res 71:3941-51

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