Aromatase in breast cancer tissue ? localization and relationship with reproductive status of patients

Berstein, Lev M.; Larionov, Alexey; Kyshtoobaeva, A. Sh.; Pozharisski, Kazymir M.; Семиглазов, Владимир; Иванова, О. А.

doi:10.1007/bf01187162

Cited by 25 publications

(15 citation statements)

References 13 publications

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“…Immunohistochemical data demonstrated high focal levels of aromatase staining and supported the concept that aromatase might act in an autocrine or paracrine fashion in breast tissue (Estaban et al 1992, Santen et al 1994, Berstein et al 1996.…”

Section: Importance Of In Situ Aromatase In Breast Tissuesupporting

confidence: 52%

The potential of aromatase inhibitors in breast cancer prevention.

Santen¹,

Yue²,

Naftolin³

et al. 1999

Endocrine-Related Cancer

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Substantial evidence supports the concept that estrogens cause breast cancer in animals and in women but the precise mechanism is unknown. The most commonly held theory is that estrogens stimulate proliferation of breast cells and thus statistically increase the chances for genetic mutations which could result in cancer. Another theory is that estrogen metabolism generates oxygen-free radicals and quinones which produce both stable and unstable DNA adducts. Both result in genetic mutations which accumulate and could ultimately cause cancer. A major criticism of the latter hypothesis is that breast tissue contains insufficient concentrations of estrogen for accumulation of genotoxic metabolites. Our hypothesis is that breast tissue estrogen levels, as a result of in situ synthesis, are much higher than previously thought. We and others have shown that estrogen can be made in the breast itself through conversion of androgens to estrogens, a process catalyzed by the enzyme aromatase. The levels of estrogen in the breast increase when aromatase is overexpressed. With sufficient amounts of aromatase in breast tissue, enough estradiol as substrate should be available to allow formation of substantial amounts of genotoxic metabolites. We postulate that aromatase overexpression may in this way cause breast cancer. As evidence supporting this concept, four animal models of aromatase overexpression and either breast cancer or premalignant lesions have been described. We have provided evidence that normal breast tissue can make estrogen and that certain stimulatory compounds can increase aromatase activity in the breast by nearly 10,000-fold. If our concepts are correct, it might be possible to prevent breast cancer by blocking the aromatase enzyme. Drugs are currently available to inhibit aromatase nearly completely without causing significant side-effects. Aromatase inhibitors might be more effective than antiestrogens in preventing breast cancer because of their dual role to block both initiation and promotion of breast cancer. To inhibit the initiation process, these inhibitors would reduce levels of the genotoxic metabolites of estradiol by lowering estradiol concentrations in tissue. At the same time, aromatase inhibitors would inhibit the process of tumor promotion by lowering tissue levels of estradiol and thus blocking cell proliferation. These concepts provide a strong rationale for studies of aromatase inhibitors to prevent breast cancer.

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Section: Importance Of In Situ Aromatase In Breast Tissuesupporting

confidence: 52%

The potential of aromatase inhibitors in breast cancer prevention.

Santen¹,

Yue²,

Naftolin³

et al. 1999

Endocrine-Related Cancer

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“…Elevated activity of aromatase, both in the fatty components and in the epithelial cells, has been associated with a 10-fold higher concentration of estradiol in breast cancer tissue than in plasma and normal tissue. 28,29 Consequently, 83% of estrogen found in breast tumors could result from in situ aromatase. 30 Estradiol and estrone in breast cancer tissues can be efficiently converted to their hydroxyestrogens equivalents.…”

Section: Discussionmentioning

confidence: 99%

Invasiveness of breast cancer cells MDA‐MB‐231 through extracellular matrix is increased by the estradiol metabolite 4‐hydroxyestradiol

Paquette

Bisson

Baptiste

et al. 2004

Intl Journal of Cancer

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In malignant breast cancer, estrogen metabolism is altered, favoring the accumulation of hydroxyestradiols, which can generate free radicals. These reactive species can activate matrix metalloproteinases (MMPs), which in turn can hydrolyze the proteins of the extracellular matrix (ECM) that act as a barrier to tumor cell passage. The aim of this study was to determine whether reactive oxygen species generated by 4-hydroxyestradiol (4-OHE 2 ) can activate MMP-2 and then enhance the invasiveness of breast cancer cells MDA-MB-231 in vitro. Invasion and metastases development require the degradation of the extracellular matrix (ECM), which acts as a barrier to tumor cell passage. ECM consists of interstitial matrix and basement membrane (BM). The first step of tumor invasion is characterized by the degradation of BM components, particularly type IV collagen, laminin and proteoglycan. 1 Cancer cells can then migrate through the interstitial matrix by breaking down its protein components and then either entering the lymphatic capillaries or migrating a second time through BM to reach the blood stream.ECM proteins can be degraded by proteases, mainly the matrix metalloproteinases (MMPs). 2,3 In breast cancer, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9 and MMP-13 are frequently detected; however, their respective importance for breast cancer progression still needs to be investigated. 4 -6 Nevertheless, the expression of MMP-2 has been linked to invasiveness of breast carcinoma cells, and its detection in breast carcinoma tissue was associated with a shortened recurrence-free survival. 7,8 MMPs are released under an inactive form (proMMPs) by cancer cells, but also by the stroma, i.e., fibroblast and endothelial cells. 9,10 Under their inactive proMMP forms, the propeptide domain covers the active site blocking access to substrate. This configuration is stabilized through the interaction between a cysteine located at a key position in the propeptide and a zinc atom at the MMP active site. 11,12 Expression and activation of proMMPs are considered to be important steps in metastases development. 2 It is proposed that proMMP-2 activation involves the cleavage of its propeptide by a membrane type 1-matrix metalloproteinase (MT1-MMP) molecule located on cell surfaces. ProMMP-2 binds to MT1-MMP using TIMP-2 as an adaptor by forming a trimolecular complex on the cell surface. 13 In this complex, the N-terminal domain of the tissue-inhibitor of matrix metalloproteinase 2 (TIMP-2) binds the catalytic domain of MT1-MMP and its C-terminal domain binds the hemopexin-like domain of proMMP-2. Another MT1-MMP near the complex cleaves the propeptide bond of proMMP-2 and generates an intermediate form, which is then converted into a fully active enzyme by an autoproteolytic mechanism. Consequently, active MMP-2 is then located directly at the migration front. 13,14 On the other hand, TIMP-2 plays a dual role since it can also inhibit MMP-2 by forming noncovalent associations with the active site of the MMP-2.ProMMP activation can also be achiev...

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“…Preliminary immunocytochemical studies could not convincingly demonstrate aromatase in lymphocytes of normal breast tissue from women undergoing reduction mammoplasty (Price et al 1992) or tumor-associated lymphocytes in breast cancer patients (Santen et al 1994;Berstein et al 1996), and were evaluated as equivocal. Later, Berstein et al ) investigated androstenedione conversion in lymphocytes and aromatase activity in tumor tissue by the release of tritiated-water from 3 H-1b-androstenedione.…”

Section: Discussionmentioning

confidence: 99%

“…Earlier -in collaboration with the group of Dr. R.Santen -we proposed the so-called ''three-component model'' of estrogen formation in breast tumors. This model postulated that besides epithelial (Esteban et al 1992;Berstein et al 1996) and stromal (Santen et al 1994(Santen et al , 1997 cells, the total estrogenic tumor pool has input from the cells of lymphocyticmacrophagal infiltrate (Berstein et al 1995). While the role of macrophages as a source of extragonadal estrogen production is demonstrated rather convincingly (Mor et al 1998), the clear evidence of this in relation to lymphocytes and -specifically -to tumor-infiltrating lymphocytes (TIL) has not been presented.…”

Section: Introductionmentioning

confidence: 99%