TGF-BETA AND BCSCS · A study of TGF-beta effects on breast cancer stem cells

A study of TGF-beta effects on breast cancer stem cells

Project context and objectives By developing this project, I have successfully analysed the role and identified the molecular determinants of the TGF-beta pathway in the regulation of human breast cancer stem cells (BCSCs). Cancer stem cells (CSC) are tumour cells that share features with normal stem cells such as the ability to self-renew and give rise to all cell types that compose a particular cancer sample. These cells have a tumour-initiating capacity and have been proposed to also be responsible for cancer metastasis and relapse. Conventional chemio-therapeutic drugs target differentiated or differentiating cells, which form the bulk of the tumour but lack the ability to generate new cancer cells, leaving the CSC population untouched and able to cause a relapse of the disease. This urgently demands an increase in our knowledge of the biology of these cells in order to improve cancer treatment and prognosis. Human breast cancer is a heterogeneous malignancy with at least five different subtypes (luminal A, luminal B, ERBB2, basal and claudin-low) described. It has been suggested that this heterogeneity results from different breast tumour subtypes originating in cells within distinct compartments of the mammary epithelium. Recent data supports this hypothesis by strongly suggesting that mammary stem cells (MaSC) and luminal progenitors are the cell of origin of claudin-low and basal-like tumours, respectively. This indicates that CSC are not always derived from a MaSC but could originate from a more differentiated normal cell acquiring self-renewal and other stem cell-like traits. Work performed and main results To uncover the role of the TGF-beta pathway in BCSCs, I used a range of cell lines that represent the molecular heterogeneity of human breast tumours and showed TGF-beta promotes BCSC activity only in the claudin-low molecular subtype, a very rare and aggressive subtype of breast cancer. TGF-beta effect in these cells is achieved by its specific transcription factors, Smads, which orchestrate the regulation of specific genes (TbSC-A signature) associated with BCSC expansion. Significantly, TbSC-A predicts a worse clinical outcome and is enriched in claudin-low breast tumours compared to other breast cancer molecular subtypes. Mechanistically, I showed NEDD9 is necessary and sufficient for a TGF-beta-mediated increase in BCSC activity through a positive feedback loop that integrates Smad and SRF-dependent signals. Interestingly in MDA-MB-231, one of the cell lines with TGF-beta-induced BTIC activity, MRTF-SRF transcriptional activation of several target genes was previously shown to be required for experimental metastasis. Therefore we propose that therapeutic targeting of both Rho family GTPases and TGF-beta signalling might be an attractive strategy to eliminate breast cancer metastasis in claudin-low breast cancers, by both suppressing the spreading of cancer cells and the self-renewal of the BTIC population. Similar opposing effects were observed in normal human mammary epithelial cell subpopulation. I observed TGF-beta increases the number of MaSCs and inhibits luminal progenitor numbers in both the mouse and the normal human mammary gland, revealing conserved responses to TGF-beta in both malignant and normal mammary epithelial cells. This data further supports MaSC, which increase their stem cell activity in response to TGF-beta and are the cell of origin of the claudin-low molecular subtype.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз