ABSTRACT
SOX11 is an embryonic mammary epithelial marker that is normally silenced prior to birth. High SOX11 levels in breast tumours are significantly associated with distant metastasis and poor outcome in breast cancer patients. Here, we show that SOX11 confers distinct features to ER-negative DCIS.com breast cancer cells, leading to populations enriched with highly plastic hybrid epithelial/mesenchymal cells, which display invasive features and alterations in metastatic tropism when xenografted into mice. We found that SOX11+DCIS tumour cells metastasize to brain and bone at greater frequency and to lungs at lower frequency compared to cells with lower SOX11 levels. High levels of SOX11 leads to the expression of markers associated with mesenchymal state and embryonic cellular phenotypes. Our results suggest that SOX11 may be a potential biomarker for breast tumours with elevated risk of developing metastases and may require more aggressive therapies.
Subject(s)
Breast Neoplasms , Epithelial-Mesenchymal Transition/genetics , Neoplasm Invasiveness/pathology , SOXC Transcription Factors/metabolism , Animals , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/metabolism , Carcinoma, Intraductal, Noninfiltrating/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Heterografts , Humans , Mice , SOXC Transcription Factors/genetics , SOXC Transcription Factors/pharmacologyABSTRACT
Many inflammation-associated diseases, including cancers, increase in women after menopause and with obesity. In contrast to anti-inflammatory actions of 17ß-estradiol, we find estrone, which dominates after menopause, is pro-inflammatory. In human mammary adipocytes, cytokine expression increases with obesity, menopause, and cancer. Adipocyte:cancer cell interaction stimulates estrone- and NFκB-dependent pro-inflammatory cytokine upregulation. Estrone- and 17ß-estradiol-driven transcriptomes differ. Estrone:ERα stimulates NFκB-mediated cytokine gene induction; 17ß-estradiol opposes this. In obese mice, estrone increases and 17ß-estradiol relieves inflammation. Estrone drives more rapid ER+ breast cancer growth in vivo. HSD17B14, which converts 17ß-estradiol to estrone, associates with poor ER+ breast cancer outcome. Estrone and HSD17B14 upregulate inflammation, ALDH1 activity, and tumorspheres, while 17ß-estradiol and HSD17B14 knockdown oppose these. Finally, a high intratumor estrone:17ß-estradiol ratio increases tumor-initiating stem cells and ER+ cancer growth in vivo. These findings help explain why postmenopausal ER+ breast cancer increases with obesity, and offer new strategies for prevention and therapy.
Subject(s)
Breast Neoplasms/metabolism , Estrogens/metabolism , Inflammation/metabolism , Obesity/metabolism , Postmenopause/metabolism , Premenopause/metabolism , Animals , Cells, Cultured , Female , Humans , Mice , Mice, Congenic , Mice, Inbred C57BL , Mice, TransgenicABSTRACT
Increased cancer stem cell content during development of resistance to tamoxifen in breast cancer is driven by multiple signals, including Sox2-dependent activation of Wnt signalling. Here, we show that Sox2 increases and estrogen reduces the expression of the transcription factor Sox9. Gain and loss of function assays indicate that Sox9 is implicated in the maintenance of human breast luminal progenitor cells. CRISPR/Cas knockout of Sox9 reduces growth of tamoxifen-resistant breast tumours in vivo. Mechanistically, Sox9 acts downstream of Sox2 to control luminal progenitor cell content and is required for expression of the cancer stem cell marker ALDH1A3 and Wnt signalling activity. Sox9 is elevated in breast cancer patients after endocrine therapy failure. This new regulatory axis highlights the relevance of SOX family transcription factors as potential therapeutic targets in breast cancer.
Subject(s)
Breast Neoplasms/metabolism , Breast/metabolism , Drug Resistance, Neoplasm , Neoplastic Stem Cells/metabolism , SOX9 Transcription Factor/metabolism , SOXB1 Transcription Factors/metabolism , Breast/cytology , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cell Line , Cell Proliferation , Epithelial Cells/cytology , Estrogens/pharmacology , Female , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , SOX9 Transcription Factor/genetics , Signal Transduction , Tamoxifen/pharmacology , Up-RegulationABSTRACT
The SRC-family kinase LYN is highly expressed in triple-negative/basal-like breast cancer (TNBC) and in the cell of origin of these tumors, c-KIT-positive luminal progenitors. Here, we demonstrate LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress. LYN activity is modulated by PIN1, a prolyl isomerase, and in BRCA1 mutant TNBC PIN1 upregulation activates LYN independently of c-KIT. Furthermore, the full-length LYN splice isoform (as opposed to the Δaa25-45 variant) drives migration and invasion of aggressive TNBC cells, while the ratio of splice variants is informative for breast cancer-specific survival across all breast cancers. Thus, dual mechanisms-uncoupling from upstream signals and splice isoform ratios-drive the activity of LYN in aggressive breast cancers.
Subject(s)
Breast Neoplasms/enzymology , Breast Neoplasms/pathology , src-Family Kinases/metabolism , Adolescent , Adult , Animals , BRCA1 Protein/deficiency , BRCA1 Protein/metabolism , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Movement , Cell Proliferation , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Gene Expression Regulation, Neoplastic , HEK293 Cells , Humans , Isoenzymes/metabolism , Mice , NIMA-Interacting Peptidylprolyl Isomerase/metabolism , Neoplasm Invasiveness , Proto-Oncogene Proteins c-kit/metabolism , RNA Splicing/genetics , Survival Analysis , Up-Regulation , Young Adult , src-Family Kinases/geneticsABSTRACT
New strategies in regenerative medicine include the implantation of stem cells cultured in bio-resorbable polymeric scaffolds to restore the tissue function and be absorbed by the body after wound healing. This requires the development of appropriate micro-technologies for manufacturing of functional scaffolds with controlled surface properties to induce a specific cell behavior. The present report focuses on the effect of substrate topography on the behavior of human mesenchymal stem cells (MSCs) before and after co-differentiation into adipocytes and osteoblasts. Picosecond laser micromachining technology (PLM) was applied on poly (L-lactide) (PLLA), to generate different microstructures (microgrooves and microcavities) for investigating cell shape, orientation, and MSCs co-differentiation. Under certain surface topographical conditions, MSCs modify their shape to anchor at specific groove locations. Upon MSCs differentiation, adipocytes respond to changes in substrate height and depth by adapting the intracellular distribution of their lipid vacuoles to the imposed physical constraints. In addition, topography alone seems to produce a modest, but significant, increase of stem cell differentiation to osteoblasts. These findings show that PLM can be applied as a high-efficient technology to directly and precisely manufacture 3D microstructures that guide cell shape, control adipocyte morphology, and induce osteogenesis without the need of specific biochemical functionalization.
