The overall goal of this proposal is to test whether targeting individual cell cycle proteins represents a highly selective therapeutic strategy in different types of human breast cancer. The proliferation of mammalian cells is driven by the core cell cycle machinery operating in cell nucleus. The key components of this machinery are proteins called cyclins, which bind, activate and provide substrate specificity to their associated cyclin-dependent kinases (CDKs). These cyclin-CDK complexes phosphorylate cellular proteins, thereby driving cell proliferation. Mouse gene knockout experiments demonstrated that individual cyclins and CDKs are dispensable for development and for normal proliferation of the majority of cell types. In contrast, these proteins are essential for the initiation and for maintenance of specific cancer types, depending on the genetic lesion they carry. Relevant for this application, our laboratory recently demonstrated that an ubiquitous, global shutdown of cyclin 01 in mice bearing MMTV-Erb82 (HER2) driven breast cancers blocked tumor cell proliferation and triggered tumor cell senescence, without having any obvious impact on animals'physiology. Importantly, administration of an inhibitor of CDK4 and CDK6 (PD 0332991) to tumor bearing animals had the same effect, namely it caused senescence of Erb82-driven breast cancer cells. These observations suggest that inhibition of CDK4/6 kinase activity may represent a very effective therapeutic strategy in women with HER2-positive (HER2+) breast cancers. In the work proposed in Aim 1, we will extend our analyses to human HER2+ breast cancers. We will take advantage of a very large collection of human breast cancer cell lines (including several HER2+) assembled by Dr. Polyak. We will also use xenografts of primary HER2+ breast cancers, to test the effect of CDK4/6 inhibition on human mammary carcinomas. Lastly, we will elucidate how human HER2+ breast cancer cells develop resistance to CDK4/6 inhibition.
In Aim 2, we will extend our approach to triple-negative breast cancers, where very few therapeutic options are available. We will test our hypothesis that this specific cancer type depends of cyclin E-CDK1 and/or A-CDK1 kinase.
The Specific Aims are:
Aim 1. To determine the response of human Erb82-positive (HER2+) breast cancers to cyclin D-CDK4/6 inhibition;
Aim 2. To study the requirement for CDK1 function in triple-negative breast cancers
In this study we will test our hypothesis that HER2+ human breast cancers critically depend on CDK4/6 kinase, while triple-negative breast cancers require CDK1. If our hypotheses are confirmed, this study may lead to novel therapeutic strategies for women with HER2+ and with triple-negative breast cancers.
|Bailey, Shannon T; Westerling, Thomas; Brown, Myles (2015) Loss of estrogen-regulated microRNA expression increases HER2 signaling and is prognostic of poor outcome in luminal breast cancer. Cancer Res 75:436-45|
|Hines, William C; Su, Ying; Kuhn, Irene et al. (2014) Sorting out the FACS: a devil in the details. Cell Rep 6:779-81|
|Yamamoto, Shoji; Wu, Zhenhua; Russnes, Hege G et al. (2014) JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell 25:762-77|
|Jeselsohn, Rinath; Yelensky, Roman; Buchwalter, Gilles et al. (2014) Emergence of constitutively active estrogen receptor-? mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 20:1757-67|
|Lu, Haihui; Clauser, Karl R; Tam, Wai Leong et al. (2014) A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 16:1105-17|
|Pathania, Shailja; Bade, Sangeeta; Le Guillou, Morwenna et al. (2014) BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nat Commun 5:5496|
|Hu, Yiduo; Petit, Sarah A; Ficarro, Scott B et al. (2014) PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair. Cancer Discov 4:1430-47|
|McAllister, Sandra S; Weinberg, Robert A (2014) The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol 16:717-27|
|Hill, Sarah J; Rolland, Thomas; Adelmant, Guillaume et al. (2014) Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage. Genes Dev 28:1957-75|
|Hill, Sarah J; Clark, Allison P; Silver, Daniel P et al. (2014) BRCA1 pathway function in basal-like breast cancer cells. Mol Cell Biol 34:3828-42|
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