Although in general, the larger the primary tumor the greater the likelihood that it will metastasize or already has metastasized, this is not always the case. Many small breast cancers develop metastasis and have a discouraging outcome. Characterizing genes that drive these tumors' rapid progression may identify novel biomarkers to help clinicians guide current treatments, and may offer novel therapeutic targets. Our work in the prior funding period focused on the role of the matricellular protein CCN6 in breast tumorigenesis, which was unknown. We have convincingly demonstrated that while CCN6 protein is expressed in breast epithelial cells, it is reduced or lost in 60% of invasive breast carcinomas, where it is associated with poor outcome. We have clearly shown that decreases invasion and metastasis in breast cancer in vivo and in vitro. Our preliminary data and the current proposal are consistent with the long-term objectives of this laboratory: to understand basic mechanisms associated with breast cancer progression and translate them into clinical utility. We have shown that downregulation of CCN6 in nontumorigenic breast cells disrupts normal acinar organization and triggers an epithelial to mesenchymal transition (EMT) and invasion, which requires BMP4-mediated activation of TAK1 and p38 pathway, known to promote metastasis. Our laboratory has provided the first mechanistic link between CCN6 and BMP4 signaling in humans. CCN6 binds to BMP4 protein in breast cancer cells and reduces invasion. However, the mechanistic details and in vivo consequences of this interaction to breast cancer metastasis need further investigation. The overall goal of the current proposal is to determine the potential mechanisms whereby CCN6 reduces breast cancer metastasis and to translate biologic findings into the clinical field. The central hypothesis is that CCN6 suppresses breast cancer progression by binding to BMP4 and antagonizing the effect of BMP4-mediated activation of TAK1 and p38 kinases on EMT, invasion, migration, and metastasis. We propose the following three hypothesis-driven specific aims.
AIM 1 : To investigate the in vivo consequences of CCN6 conditional knockout in the mammary gland and to define the critical CCN6 protein motifs involved in breast cancer progression.
AIM 2 : To determine the mechanism of CCN6-mediated metastasis suppressor function in vivo and its relationship to BMP4/TAK1/p38 signaling.
AIM 3 : To ascertain the translational impact of CCN6 and the BMP4 pathway in human breast tissue samples. We will investigate the effect of CCN6 on the EMT, invasion and metastasis and on BMP4/TAK/p38 signaling in vivo using unique human tissue resources. Regulating the expression of CCN6 may represent an important drug target for prevention and/or reduction of breast cancer metastasis. With more than 1.2 million women diagnosed this year worldwide, these studies have the potential of providing better diagnosis, more accurate prognostication, and pave the way for future development of small molecules based on CCN6.

Public Health Relevance

Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. Previously, our work demonstrated that CCN6, a protein produced in the breast epithelium and secreted into the extracellular environment, is reduced or lost in 60% of invasive carcinomas of the breast. We found that CCN6 can reduce breast cancer metastasis. The work proposed will provide a molecular basis for the use of CCN6 and its downstream pathway in drug development and for new tissue- based tests for breast cancer metastasis. If we could prevent the loss of CCN6 or reactivate it in metastasizing tumors we would greatly improve breast cancer outcome and save the lives of millions of women.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125577-10
Application #
9388323
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2006-12-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Gonzalez, Maria E; Martin, Emily E; Anwar, Talha et al. (2017) Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth. Cell Rep 18:1215-1228
Martin, E E; Huang, W; Anwar, T et al. (2017) MMTV-cre;Ccn6 knockout mice develop tumors recapitulating human metaplastic breast carcinomas. Oncogene 36:2275-2285
Kleer, Celina G (2016) Dual roles of CCN proteins in breast cancer progression. J Cell Commun Signal 10:217-222
Peng, Dongjun; Tanikawa, Takashi; Li, Wei et al. (2016) Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells through IL6/STAT3 and NO/NOTCH Cross-talk Signaling. Cancer Res 76:3156-65
Gonzalez-Guerrico, Anatilde M; Espinoza, Ingrid; Schroeder, Barbara et al. (2016) Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer. Oncotarget 7:71151-71168
Huang, Wei; Martin, Emily E; Burman, Boris et al. (2016) The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells. Oncotarget 7:25180-93
Cani, Andi K; Hovelson, Daniel H; McDaniel, Andrew S et al. (2015) Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors. Mol Cancer Res 13:613-9
Yang, Cheng-Chieh; LaBaff, Adam; Wei, Yongkun et al. (2015) Phosphorylation of EZH2 at T416 by CDK2 contributes to the malignancy of triple negative breast cancers. Am J Transl Res 7:1009-20
Proctor, Erica; Kidwell, Kelley M; Jiagge, Evelyn et al. (2015) Characterizing Breast Cancer in a Population with Increased Prevalence of Triple-Negative Breast Cancer: Androgen Receptor and ALDH1 Expression in Ghanaian Women. Ann Surg Oncol 22:3831-5
Menon, Rajasree; Panwar, Bharat; Eksi, Ridvan et al. (2015) Computational Inferences of the Functions of Alternative/Noncanonical Splice Isoforms Specific to HER2+/ER-/PR- Breast Cancers, a Chromosome 17 C-HPP Study. J Proteome Res 14:3519-29

Showing the most recent 10 out of 37 publications