Regional cyclin D1 overexpression or hypoxia correlate inversely with heterogeneous oestrogen receptor-alpha expression in human breast cancer.
The oestrogen receptor-alpha (ER alpha) differs in expression and regulation in breast cancer and, by studying the co-factor cyclin D1 as well as changes in the microenvironment, we here delineate two conditions that potentially cause regional down-regulation of the receptor. Heterogeneously expressed ER alpha was observed in 24 out of 134 of the studied breast cancer samples. In 6 out of 24 of the heterogeneous tumours, there was a clear inverse association between cyclin D1 protein/gene amplification and presence of ER alpha. In a subset of 120 tumours, analysed by Western blotting and ELISA, we further showed disparity in differentiation grade and proliferation between tumours with varied cyclin D1/ER alpha content. In another fraction (9 out of 24) of the heterogeneous tumours, there was an inverse association between the ER alpha and Hypoxia-Inducible Factor-1 alpha (HIF-1 alpha) suggesting that ER alpha was down-regulated during hypoxic conditions. These results were verified by culturing ER alpha breast cancer cell lines under hypoxic conditions showing a prominent down-regulation of the ER alpha. The two factors linked to ER alpha down-regulation can also be used to design new treatment approaches interfering with key proteins in these ER alpha regulatory pathways, thereby hopefully increasing the effect of anti-hormonal treatment.
Kronblad
Asa
A
Division of Pathology, Lund University, Malmö University Hospital, S-20502, Malmö, Sweden.
Helczynska
Karolina
K
Nielsen
Niels Hilmer
NH
Påhlman
Emdin
E
Emdin
Stefan
S
Påhlman
Sven
S
Landberg
Göran
G
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D047628:Estrogen Receptor alpha; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009367:Neoplasm Staging; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011960:Receptors, Estrogen; D014157:Transcription Factors; D019938:Cyclin D1