Breast cancer (BC), a genetically heterogeneous disease, is the most commonly identified malignant disease in Western women after non-melanocytic skin cancer. It attacks one in eight women (~12%), impacting nearly every family worldwide, including the US Veterans population. Approximately 30% of those diagnosed will develop the invasive form of the disease, which is ultimately incurable. Therefore, it is a major health issue for women Veterans. Although increased early diagnosis and new therapeutic regimens have significantly improved BC survival, the therapeutic options for advanced stage BC are limited. One reason these regimens are not effective is that they do not target the tumor microenvironment, which plays critical roles in tumor progression. Thus, there is a need to understand the etiology of BC progression from a non- invasive microenvironment and to use this awareness for the design of a targeted, molecular based therapy. We recently discovered that the matricellular protein CCN5 is highly expressed in non-invasive BC cell lines and tissue samples, as compared to invasive ones and plays a negative regulator of plasticity in vitro. It prevents the epithelial to mesenchymal transition (EMT) process in BC cells. Furthermore, preliminary studies suggest that CCN5 may inhibit the transition of in situ ductal carcinoma (DCIS) to invasive BC through the protection of biological fences (myoepithelial layer and basement membrane), or may prevent or reduce the growth of aggressive BC cells or both and possibly make ER negative aggressive BC cells sensitive to hormone therapy. Now, we propose to establish the above premises and unravel the mechanisms of CCN5 in regulation of cancer cell progression to invasion using a xenograft model, genetically engineered mouse models, genetically manipulated human BC cell lines and stromal cells. To test this hypothesis, three specific aims are proposed:
Aim 1 : We will determine whether CCN5 is able to prevent DCIS to invasive ductal carcinoma transition by protecting the myoepithelial layer or basement membrane degradation or both. To test this, conditional knock- down strategies will be used in a MCFDCIS-intraductal-xenograft model (MIND model).
Aim 2 : We will determine the effect of CCN5 on tumor progression and survival in BC. To test this, we will use the MMTV-neu/Tet-op-MMTV-CCN5 (MNIC5) transgenic mouse model to evaluate the impact of CCN5 gains in HER-2/neu driven mammary tumorigenesis.
Aim 3 : We will determine whether the gain of CCN5 re-sensitizes antiestrogen's action on BC. Both in vitro and in vivo (xenografts and MNIC5 mouse model) will be used. We will use state-of-the art techniques, our development of a Tet-op-MMTV-CCN5 mouse model, and the unique collective expertise of our multi-disciplinary team to uncover the role of the CCN5 pathway in BC progression. Significance: The proposed studies should result in new explanations of the protective role of CCN5 signaling in microenvironment of invasive cancers. Moreover, this study should clarify the functional roles of CCN5, while revealing novel targets and pathways which will aid in our research goals of finding effective therapeutic reagents to battle breast cancer bringing an improved prognosis to US Veterans and other pre- and post- menopausal patients.

Public Health Relevance

Despite a striking improvement in our skill to detect breast cancer, the transition of DCIS to invasive cancer to metastasis as well as resistance to hormone therapy is a poorly understood event. By revealing the mechanism of the progression of the disease and its resistance to hormone therapies, the proposed study aims to demonstrate CCN5 signaling as a novel suppressor of breast cancer progression from non-invasive to invasive transition. The results of these studies will open new venues for the treatment of breast cancer.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001989-02
Application #
8625184
Study Section
Oncology A (ONCA)
Project Start
2013-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Kansas City VA Medical Center
Department
Type
DUNS #
844272125
City
Kansas City
State
MO
Country
United States
Zip Code
64128
Haque, Inamul; Ghosh, Arnab; Acup, Seth et al. (2018) Leptin-induced ER-?-positive breast cancer cell viability and migration is mediated by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway. BMC Cancer 18:99
Ghosh, Priyanka; Banerjee, Snigdha; Maity, Gargi et al. (2017) Detection of CCN1 and CCN5 mRNA in Human Cancer Samples Using a Modified In Situ Hybridization Technique. Methods Mol Biol 1489:495-504
Das, Amlan; Dhar, Kakali; Maity, Gargi et al. (2017) Deficiency of CCN5/WISP-2-Driven Program in breast cancer Promotes Cancer Epithelial cells to mesenchymal stem cells and Breast Cancer growth. Sci Rep 7:1220
Subramanian, Arvind; Gupta, Vijayalaxmi; Sarkar, Sandipto et al. (2016) Exosomes in carcinogenesis: molecular palkis carry signals for the regulation of cancer progression and metastasis. J Cell Commun Signal 10:241-249
Hawa, Zuhair; Haque, Inamul; Ghosh, Arnab et al. (2016) The miRacle in Pancreatic Cancer by miRNAs: Tiny Angels or Devils in Disease Progression. Int J Mol Sci 17:
Banerjee, Sushanta K; Maity, Gargi; Haque, Inamul et al. (2016) Human pancreatic cancer progression: an anarchy among CCN-siblings. J Cell Commun Signal 10:207-216
Haque, I; Banerjee, S; De, A et al. (2015) CCN5/WISP-2 promotes growth arrest of triple-negative breast cancer cells through accumulation and trafficking of p27(Kip1) via Skp2 and FOXO3a regulation. Oncogene 34:3152-63
Maity, Gargi; De, Archana; Das, Amlan et al. (2015) Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition. Lab Invest 95:702-17
Banerjee, Sushanta K (2015) Dopamine: an old target in a new therapy. J Cell Commun Signal 9:85-6
Maity, Gargi; Mehta, Smita; Haque, Inamul et al. (2014) Pancreatic tumor cell secreted CCN1/Cyr61 promotes endothelial cell migration and aberrant neovascularization. Sci Rep 4:4995

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