TY - JOUR
T1 - Paracrine-stimulated gene expression profile favors estradiol production in breast tumors
AU - Amin, Sanober A.
AU - Huang, Chiang Ching
AU - Reierstad, Scott
AU - Lin, Zhihong
AU - Arbieva, Zarema
AU - Wiley, Elizabeth
AU - Saborian, Hossain
AU - Haynes, Ben
AU - Cotterill, Helen
AU - Dowsett, Mitch
AU - Bulun, Serdar E.
N1 - Funding Information:
We thank Seby Edassery, Peter Larson, JianFeng Zhou, Siby Sebastian and Bilgin Gurates at the University of Illinois at Chicago and Yong Zeng, Bob Meyer and Bernice Frederick at Northwestern University for their technical support. We also thank Stacey Tobin, Meagan Porter, Heather Rich and Ruth Grigson for editorial assistance. Supported in part by the NCI grant CA67167 and grants from the Northwestern Memorial Foundation, AVON Foundation, Lynn Sage Foundation and Friends of Prentice.
PY - 2006/7/11
Y1 - 2006/7/11
N2 - Paracrine interactions between adipose fibroblasts and malignant epithelial cells are essential for structural and hormonal support of breast tumors. Factors derived from malignant epithelial cells inhibit adipogenic differentiation of fibroblasts and upregulate expression of aromatase, which stimulates estrogen synthesis and creates a localized, growth-stimulatory environment. Here, we characterized the gene expression profile of breast adipose fibroblasts in an in vitro model of malignancy to identify other paracrine interactions that support tumor growth. Primary breast adipose fibroblasts from cancer-free women were treated with conditioned media from malignant breast epithelial cells or normal breast epithelial cells, and differences in gene expression were identified by microarray. A total of 79 differentially regulated genes encoding cytokines, enzymes, angiogenic factors, cytoskeletal proteins, extra-cellular matrix remodeling proteins, signal transduction proteins and cell surface receptors were identified, and 6 of these were verified by real-time PCR. Among these, the expression of aldo-keto reductase family 1, member C3 (AKR1C3) was upregulated. AKR1C3 has multiple enzymatic properties, including conversion of estrone to estradiol and androstenedione to testosterone. Immunoreactive AKR1C3 was detected in epithelial and stromal components of benign lesions and ductal carcinomas in situ, and in 59.8% of epithelial and 69.6% of stromal cells in invasive breast carcinomas. AKR1C3 expression was significantly higher in myoepithelial cells surrounding the neoplastic epithelium of ductal carcinoma in situ compared with those surrounding benign epithelial lesions. Importantly, AKR1C3 and aromatase mRNA levels correlated positively in 61 malignant breast tumors (R = 0.3967, p = 0.00156). Malignant epithelial cell-conditioned medium significantly increased formation of testosterone and estradiol from androstenedione in breast adipose fibroblasts. In conclusion, malignant epithelial cell-derived factors significantly upregulate the enzymes AKR1C3 and aromatase that catalyze a series of complementary reactions to convert the circulating precursor androstenedione to biologically active estradiol in vitro in the stromal fibroblasts, and in vivo, in stromal component of breast tumors.
AB - Paracrine interactions between adipose fibroblasts and malignant epithelial cells are essential for structural and hormonal support of breast tumors. Factors derived from malignant epithelial cells inhibit adipogenic differentiation of fibroblasts and upregulate expression of aromatase, which stimulates estrogen synthesis and creates a localized, growth-stimulatory environment. Here, we characterized the gene expression profile of breast adipose fibroblasts in an in vitro model of malignancy to identify other paracrine interactions that support tumor growth. Primary breast adipose fibroblasts from cancer-free women were treated with conditioned media from malignant breast epithelial cells or normal breast epithelial cells, and differences in gene expression were identified by microarray. A total of 79 differentially regulated genes encoding cytokines, enzymes, angiogenic factors, cytoskeletal proteins, extra-cellular matrix remodeling proteins, signal transduction proteins and cell surface receptors were identified, and 6 of these were verified by real-time PCR. Among these, the expression of aldo-keto reductase family 1, member C3 (AKR1C3) was upregulated. AKR1C3 has multiple enzymatic properties, including conversion of estrone to estradiol and androstenedione to testosterone. Immunoreactive AKR1C3 was detected in epithelial and stromal components of benign lesions and ductal carcinomas in situ, and in 59.8% of epithelial and 69.6% of stromal cells in invasive breast carcinomas. AKR1C3 expression was significantly higher in myoepithelial cells surrounding the neoplastic epithelium of ductal carcinoma in situ compared with those surrounding benign epithelial lesions. Importantly, AKR1C3 and aromatase mRNA levels correlated positively in 61 malignant breast tumors (R = 0.3967, p = 0.00156). Malignant epithelial cell-conditioned medium significantly increased formation of testosterone and estradiol from androstenedione in breast adipose fibroblasts. In conclusion, malignant epithelial cell-derived factors significantly upregulate the enzymes AKR1C3 and aromatase that catalyze a series of complementary reactions to convert the circulating precursor androstenedione to biologically active estradiol in vitro in the stromal fibroblasts, and in vivo, in stromal component of breast tumors.
KW - AKR1C3
KW - Aromatase
KW - Breast adipose fibroblast
KW - Breast cancer
KW - Epithelial-stromal interaction
KW - Estrogen
UR - http://www.scopus.com/inward/record.url?scp=33745403240&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745403240&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2006.04.029
DO - 10.1016/j.mce.2006.04.029
M3 - Article
C2 - 16735089
AN - SCOPUS:33745403240
VL - 253
SP - 44
EP - 55
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
IS - 1-2
ER -