A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription [published erratum appears in J Clin Endocrinol Metab 1994 Feb;78(2):494]
SE Bulun, TM Price, J Aitken, MS Mahendroo and ER Simpson
Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas 75235-9051.
C19 steroids are converted to estrogens in a number of tissues by a
specific form of cytochrome P450, namely aromatase cytochrome P450
(P450arom). Adipose tissue is the principal site of estrogen formation in
postmenopausal women. Aromatase activity as well as P450arom transcripts
primarily reside in the stromal cell component of the adipose tissue.
Studies designed to investigate whether increased local aromatase activity
in breast adipose tissue influences the growth of breast cancers have
yielded discrepant results. In an attempt to clarify this controversy,
adipose tissue was obtained from the four breast quadrants at the time of
mastectomy (n = 13) performed for removal of a tumor. Breast fat P450arom
messenger RNA levels were quantified and compared between the four
quadrants within each specimen using competitive polymerase chain reaction
after reverse transcription in which 10 micrograms human adipose total RNA
together with 1 pg rat complementary RNA (internal standard) were reverse
transcribed and coamplified. In 9 out of 13 patients (69%), highest
P450arom transcript levels colocalized to the quadrants bearing tumors.
This correlation was statistically significant (P < 0.001). The regional
distribution of P450arom transcripts in breast adipose tissue of
disease-free individuals, obtained during reduction mammoplasty (control
group, n = 9), did not favor any particular region of the breast. We also
quantified by morphometry the histological components of the adipose tissue
samples from each quadrant in mastectomy specimens. The distribution of
stromal cells significantly correlated with the distribution of P450arom
transcript levels, in that quadrants containing highest proportions of
stromal cells matched to highest transcript levels (P < 0.01). Although
the quadrants bearing tumors contained the highest percentage of stromal
cells, this correlation was not statistically significant. The adipose
tissue surrounding a breast tumor displays increased estrogen biosynthesis,
which may promote tumor growth. It is further suggested that the
distribution of stromal cell components in breast adipose tissue gives rise
to locally elevated P450arom expression, which in turn may favor neoplastic
development and growth in these predisposed areas of the breast. The
correlation between the presence of a tumor and elevated P450arom levels in
the proximal adipose tissue is independent of tumor size, node involvement,
histological type or grade, estrogen/progesterone receptor status, DNA
index, or S-phase fraction.
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