Calcium-sensing stromal interaction molecule 2 upregulates nuclear factor of activated T cells 1 and transforming growth factor-β signaling to promote breast cancer metastasis

AbstractKisspeptins (KPs), peptide products of the kisspeptin-1 (KISS1) gene, are the endogenous ligands for the KISS1 receptor, KISS1R, which is a G protein-coupled receptor. In many human tumors, KISS1 functions as a metastasis-suppressor gene and KISS1/KISS1R signaling has antimetastatic and tumor-suppressor roles. On the contrary, emerging evidence indicates that the KP/KISS1R pathway plays detrimental roles in triple negative breast cancer (TNBC), the most difficult type of breast cancer to treat. TNBC patients initially respond to chemotherapy, but tumors acquire drug resistance and many patients relapse and die of metastases within a few years. In this review, we summarize recent developments in the understanding of the mechanisms by which KP/KISS1R signaling plays an adverse role in TNBC. This includes focusing on how KISS1R signaling regulates the cell cytoskeleton to induce tumor invadopodia formation and how KISS1R communicates with growth factor receptors such as the epidermal growth factor receptor, the receptor tyrosine kinase AXL, and transforming growth factor-β to promote cell invasion, metastasis, and drug resistance.

Download Full-text

Targeting the Transforming Growth Factor-β pathway inhibits human basal-like breast cancer metastasis

Molecular Cancer ◽

10.1186/1476-4598-9-122 ◽

2010 ◽

Vol 9 (1) ◽

pp. 122 ◽

Cited By ~ 108

Author(s):

Vidya Ganapathy ◽

Rongrong Ge ◽

Alison Grazioli ◽

Wen Xie ◽

Whitney Banach-Petrosky ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Cancer Metastasis ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Breast Cancer Metastasis ◽

Basal Like Breast Cancer

Download Full-text

Faculty Opinions recommendation of IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725408916.793526424 ◽

2016 ◽

Author(s):

Paul Kubes ◽

Justin Deniset

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Metastasis ◽

Γδ T Cells ◽

Breast Cancer Metastasis ◽

Promote Breast Cancer

Download Full-text

NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

Molecular and Cellular Biology ◽

10.1128/mcb.00912-15 ◽

2016 ◽

Vol 36 (9) ◽

pp. 1383-1394 ◽

Cited By ~ 27

Author(s):

Erik Hedrick ◽

Syng-Ook Lee ◽

Ravi Doddapaneni ◽

Mandip Singh ◽

Stephen Safe

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Nuclear Export ◽

Cancer Metastasis ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Breast Cancer Metastasis ◽

Β1 Integrin ◽

Breast Cancer Patients ◽

Β3 Integrin

Overexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor β (TGF-β) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-β independent and dependent on regulation of β1-integrin gene expression by NR4A1 which can be inhibited by the NR4A1 antagonists 1,1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and a relatedp-carboxymethylphenyl [1,1-bis(3′-indolyl)-1-(p-carboxymethylphenyl)methane (DIM-C-pPhCO2Me)] analog. The NR4A1 antagonists also inhibited TGF-β-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-β-induced cell migration. We also observed that NR4A1 regulates expression of both β1- and β3-integrins, and unlike other β1-integrin inhibitors which induce prometastatic β3-integrin, NR4A1 antagonists inhibit expression of both β1- and β3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis.

Download Full-text