Influence of hypoxia on differentiation and proliferation of non-malignant and tumor cells
Author
Summary, in English
We show that hypoxic conditions impaired acinar morphogenesis of primary and immortalized breast epithelial cells grown ex vivo on laminin-rich matrix. The hypoxic cells remained in a mitotic state, whereas proliferation ceased with acinar morphogenesis at normoxia. We found induced expression of the differentiation repressor ID1 in the undifferentiated hypoxic MCF-10A cell structures. Acinar morphogenesis was associated with global histone deacetylation whereas the hypoxic breast epithelial cells showed sustained global histone acetylation, which is generally associated with active transcription and an undifferentiated proliferative state.
Despite expression of EPOR we show here that rhEPO stimulation of breast cancer cells has no apparent effect on cell growth in vitro. When knocking down EPOR we found a decreased proliferation in ERα+ breast cancer cells only. This inhibitory effect on proliferation appeared to be mediated via a decrease in ERα-activity. EPOR knockdown further improved Tamoxifen effects on ERα-activity in one of the cell lines tested. These results are in accordance with our previous observation that high EPOR expression in tumors correlates to impaired Tamoxifen response in breast cancer patients.
We previously demonstrated that small cell lung carcinoma (SCLC) cells lack expression of HIF-2α protein, whereas HIF-1α is expressed at both acute and prolonged hypoxia. Searching for a role of HIF-1 in hypoxic SCLC cells, we investigated metabolic pathways and HIF-1 dependence. When repressing HIF1A expression, the ATP levels were not affected and SCLC cell viability did not decrease by glucose deprivation. In contrast, glutamine withdrawal drastically decreased the number of cells and increased cell death, still in a HIF-independent fashion. The tested SCLC cells are MYC or MYCL amplified and MYC overexpression is known to stimulate glutamine metabolism. Our results might further suggest that Myc overexpression overrides the need of HIF-1α expression and activity in the response of SCLC cells to hypoxia by inducing glutaminolysis and lipogenesis.
Department/s
- Department of Translational Medicine
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2013
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2013:130
Document type
Dissertation
Publisher
Molecular Medicine
Topic
- Cancer and Oncology
Keywords
- Hypoxia
- breast cancer
- EPOR
- small cell lung carcinoma
- differentiation
- proliferation
- metabolism
Status
Published
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87651-05-2
Defence date
5 December 2013
Defence time
09:15
Defence place
Medicon Village, Building 302 Lecture Hall, Lund
Opponent
- Charlotta Dabrosin (M.D., Ph.D.)