Expression of 3β-hydroxysteroid dehydrogenase-5,4-en isomerase activity by infiltrating ductal human breast carcinoma in vitro

Abstract

In order to determine whether human mammary tumors could contribute to progesterone synthesis from pregnenolone in breast cancer patients, homogenates of infiltrating ductal primary breast tumors at different stages of malignancy (Stages II and III) obtained from pre- and post-menopausal patients (n = 7, age 37-66 years) were incubated with [7n-3H]pregnenolone as substrate. Controls were heated homogenates instead of fresh homogenates. With the use of reverse-isotope dilution analysis, [3H]progesterone was isolated and characterized. No such metabolite was evident in the control incubations of heat-denatured enzymes. The extent of enzymic conversion varied from 0.02 to 4.0%. The results reveal that activity of 3beta-hydroxysteroid dehydrogenase-5,4-en isomerase that metabolizes pregnenolone to progesterone can be identified with the viable homogenates. It is suggested that there exists a potential for substantial progesterone synthesis in vivo. This conversion may be of considerable clinical, therapeutic, and pathophysiological significance in the patient with breast cancer. The biological impact of this conversion should be a high priority research objective.

Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors

“…Similar differences in progesterone metabolism and enzyme gene expressions were observed between tumorigenic and nontumorigenic breast cell lines [16]. In addition to the ability to convert progesterone to active cancer-regulating hormones, breast carcinomas are able to synthesize progesterone [34,35], which could account for its relatively high concentrations in the xenograft tumors reported here, and indicate an in situ supply of the biosynthetic precursor of 5αP and 3αHP.…”

Breast cancer size in postmenopausal women is correlated with body mass index and androgen serum levels

“…Figure 2 and Table 2 reveal another potentially important mechanism of mutual suppression: androstenedione and its precursor DHEAS are positively correlated (p < 0.001, Figure 2). The enzyme responsible for the conversion from DHEAS to androstenedione is 3β-hydroxysteroid dehydrogenase/isomerase, which is known to be expressed specifically in invasive breast cancer 33,34 . An increase of adrenal gland-derived DHEAS would consequently be followed by an intra-tumoral conversion to androstenedione and result in increased androstenedione serum levels.…”

The unique transcriptional response produced by concurrent estrogen and progesterone treatment in breast cancer cells results in upregulation of growth factor pathways and switching from a Luminal A to a Basal-like subtype

“…The secretion of progesterone in turn acts on the adrenal glands to stimulate a concomitant secondary, albeit smaller, peak of serum estrogen [ 20 ]. Evidence also suggests that the postmenopausal breast is capable of sequestering and/or synthesising progesterone and estrogen from circulating hormonal precursors [ 21 – 25 ]. Collectively, it appears most likely that PR is activated within a hormonal milieu that includes active estrogen signalling.…”