Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

Abstract

It is well known that sex steroids play important roles in the development of invasive ductal carcinoma (IDC) of the human breast. However, biological significance of sex steroids remains largely unclear in ductal carcinoma in situ (DCIS), regarded as a precursor lesion of IDC, which is partly due to the fact that the intratumoral concentration of sex steroids has not been examined in DCIS. Therefore, in this study, we first examined the intratumoral concentrations of estradiol and 5a-dihydrotestosterone (DHT) using liquid chromatography/electrospray tandem mass spectrometry in DCIS. Intratumoral concentrations of both estradiol and DHT were threefold higher in DCIS than non-neoplastic breast tissues and estrogen-producing enzymes (aromatase, steroid sulfatase, and 17b-hydroxysteroid dehydrogenase type 1 (17bHSD1)), and androgen-producing enzymes (17bHSD5 and 5a-reductase type 1 (5aRed1)) were abundantly expressed in DCIS by real-time PCR and immunohistochemical analyses. The intratumoral concentration of DHT was significantly lower in IDC than DCIS, while the expression of aromatase mRNA in carcinoma cells and intratumoral stromal cells was significantly higher in IDC than those in DCIS. Immunohistochemistry for sex steroid-producing enzymes in DCIS demonstrated that 5aRed1 immunoreactivity was positively correlated with Ki-67 labeling index and histological grade and was also associated with an increased risk of recurrence in patients with DCIS examined. Results of our study suggest that intratumoral concentrations of estradiol and DHT are increased in DCIS, which is possibly due to intratumoral production of these steroids. Therefore, estradiol and DHT may play important roles in the development of DCIS of the human breast.

Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208

“…For example, the mean concentration of E2 in the breast tumors of premenopausal patients was approximately 1.2 pmol/g tissue (that means that if the density of tumor is 2 g/mL, the in situ E2 concentration will be 2.4 nmol/L), whereas a plasma E2 concentration of approximately 0.22 nmol/L was reported in the same paper [4,5] . Similar results were obtained from other previous studies [6,7] and from our current study on MCF-7 xenograft tumors (0.36-0.48 nmol/L). However, we once investigated the effect of TM208 on SULT1A1 and SULT2A1 and found that TM208 induced the expression of SULT1A1 more significantly than that of SULT2A1 in both MCF-7 cells and MCF-7 xenograft tumors, but all of the observed increases were less than 4-fold (Figure S1-S2).…”

“…These data are neither significantly different from each other nor from the E2 level in the normal mammary fat pad (0.39±0.01 nmol/L). The absolute reduced intratumoral E2 concentration in the TM208 treatment group is not as much as the levels observed in situ for the human breasts of healthy women versus patients [4,6,7] , but the difference was statistically significant, and all the tested concentrations were within the physiological range of E2 concentration. To the best of our knowledge, we are the first group to detect the intratumoral E2 concentration in MCF-7 xenograft mice.…”

“…Therefore, intratumoral estrogens, especially 17β-estradiol (E2), play pivotal roles in the proliferation and development of hormone-dependent breast carcinoma cells [1][2][3] . Previous studies have demonstrated that the tissue concentra-tions of E2 in breast carcinomas are much higher than those found in the plasma [4,5] or normal mammary tissues [6,7] . Consequently, blocking in situ estrogen production appears to be a potent breast cancer treatment [8][9][10][11] .…”

“…Among these isoforms, estrogen sulfotransferase (EST, SULT1E1) plays the most important role in estrogen inactivation under physiological conditions due to its high affinity for estrogens [15] . In most previous studies, the intratumoral estrogen concentrations were expressed as pg/g tissue or pmol/g tissue, which can be approximately calculated at the "nanomolar" (physiological) level even if they are much higher than those found in normal mammary tissues [6,7] or plasma [4,5] . Therefore, the intratumoral sulfation of estrogen is mainly catalyzed by EST rather than other SULT isoforms.…”

Expressão da aromatase em carcinomas de mama ductais invasivo e in situ presentes na mesma mama

“…Other researchers found similar data, with significant aromatase activity ranging from 52 to 72 percent in invasive carcinoma samples. [3][4][5][6][8][9][10] As for studies that tried to assess aromatase enzyme expression in DCIS, there seems to be discrepancies in the literature. Aromatase expression analyses in 61 cases of pure DCIS found higher rates than for 101 cases of IDC.…”