Effects of Progestins and Menstrual Cycle on Fatty Acid Synthetase and Progesterone Receptor in Human Mammary Glands*

Abstract

Fatty acid synthetase (FAS) is induced by progestins in human breast cancer cell lines. To study its regulation in normal mammary glands, the FAS level was estimated by immunohistochemistry, using the biotin-streptavidin method, in ducts and lobules of normal tissues adjacent to nonproliferative benign breast lesions collected by biopsy. Rabbit polyclonal antibodies to human FAS specifically recognized the 250-kDa FAS from MCF7 cells, as shown by Western immunoblotting. An excess of purified FAS totally switched off FAS immunostaining of R5020-treated MCF7 cells, demonstrating the validity of FAS immunocytochemical detection. FAS labeling was quantified using a computer-aided image analyzer (SAMBA 2005) in 18 patients receiving progestin therapy from the 15th to the 25th day of the menstrual cycle and 26 untreated patients. In the 2 groups, FAS staining, absent of fibroblasts, was observed in the cytoplasm of epithelial cells. It was higher in lobules than in ducts and increased significantly from the follicular to the luteal phase in both structures. Progestin treatment increased FAS expression in both structures. Using monoclonal antibodies, progesterone receptor expression was measured in frozen serial sections. In patients receiving progestin treatment, the progesterone receptor level increased from the beginning of the cycle to day 14 and then decreased during the second part of the menstrual cycle, probably down-regulated by progestin, indicating a regulation similar to that in the endometrium. We conclude that FAS is induced by progestins in the ducts and lobules of human normal mammary glands as it is in human breast cancer cells. FAS may, therefore, be useful for studying the effect of progesterone in normal human mammary glands.

Influence of menstrual cycle, parity and oral contraceptive use on steroid hormone receptors in normal breast

“…This study agrees with previous reports of OR and PR reactivity in epithelial cell nuclei of normal breast tissue, commonly expressed as a low proportion of positive cells (Petersen et al, 1987;Jacquemier et al, 1990;Joyeux et al, 1990). We now extend the observations through a semiquantitative evaluation that acknowledges not only the functional integrity of TDLU as units of response, but also the heterogeneity of immunoreactive receptor presence, both within and between the units.…”

“…While a clear picture of oestrogen receptor and progesterone receptor regulation exists for endometrium (Lessey et al, 1988), the same is not true for breast. Oestrogen and progesterone receptors (OR and PR) are both present in normal human breast epithelium (Petersen et al, 1987;Jacquemier et al, 1990;Joyeux et al, 1990;Williams et al, 1991) but with lack of agreement between authors as to differences across the cycle or consistency within it. To help clarify the situation, we have carried out an immunohistochemical analysis of OR and PR in histologically normal breast tissue, related the findings to phase of the menstrual cycle, oral contraceptive (OC) use, age and parity.…”

Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis

“…13,15 We verified by immunoblot that FAS antibodies recognized the same predominant band of 250-300 kDa in cytosols prepared from breast cancer tissues, and the SKBR3 breast cancer cell line. No staining was obtained using preimmune rabbit serum (Fig.…”

“…10,11 We previously showed that FAS was induced specifically by these progestins via the PR and some growth factors but not through the ER, but both in breast cancer cell lines [12][13][14] and in vivo. 14,15 Others have then reported that FAS was overexpressed in breast cancer of poor prognosis, 16 and that its inhibition was efficient to decrease the growth of mammary tumors in rodents. 17 In a first attempt to specify at which steps these progestins might be acting in human mammary carcinogenesis, we now evaluate the expression of PR and FAS in early steps of carcinogenesis.…”

Overexpression of Fatty Acid Synthase in Oesophageal Squamous Cell Dysplasia and Carcinoma

“…Exceptions include the liver [9], adipose tissue [10], cycling endometrium [11], foetal lung with the biosynthesis of lecithin [12] and lactating mammary gland [13,14].…”