Paradoxial changes in the expression of estrogen receptor alpha in breast cancer multicellular spheroids.
Multicellular spheroids are excellent models for the analysis of cancer behavior. Just like small avascular tumors, they present a marked zonal heterogeneity which influences gene expression and thus, growth and response to chemotherapy. In the present paper, we sought to analyze the effects of three-dimensional culture in the expression and distribution of estrogen receptor alpha. Using MCF-7 breast cancer cells, we found that multicellular spheroids in estrogen-containing medium presented a paradoxical regulation of estrogen receptor alpha, with a decrease in protein expression and a marked increase in mRNA steady-state levels. Immunohistochemistry showed that only sparse cells in the periphery of the spheroid expressed estrogen receptor, in sharp contrast with progesterone receptor, which was more extensively expressed and HIF-alpha, which was expressed in the central core of the spheroid. This could mean that both hypoxia and ERA activation by estrogen participate in the expression heterogeneity of this hormone receptor in breast cancer These results are important to considerate in the analysis and interpretation of immunohistochemistry of ERA and downstream targets in samples of solid tumors.
Muñoz
Laura
L
Molecular Biology Laboratory, Sub-Direction of Basic Research, National Institute of Cancerology, Av. San Fernando 22, Tlalpan 14080, Mexico City, Mexico.
Espinosa
Magali
M
Quintanar-Jurado
Valeria
V
Hidalgo
Alfredo
A
Melendez-Zajgla
Jorge
J
Maldonado
Vilma
V
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000096:biosynthesis; D018874:Spheroids, Cellular / Q000378:metabolism*
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D011980:Receptors, Progesterone