Alfredo Molinolo

Induction of mammary adenocarcinomas by medroxyprogesterone acetate in BALBc female mice

In a previous paper we reported that medroxyprogesterone acetate (MPA) decreased the incidence of foreign body tumorigenesis in BALB/c mice but that mammary adenocarcinomas appeared in some of the females. The experiment was repeated in 245 virgin females as follows: (1) 40 mice treated with 40 mg of MPA depot s.c. every 2 months during a whole year; (2) 117 mice bearing a foreign body (FB) and treated with MPA; (3) 46 mice bearing a FB; (4) 42 non-treated mice. Mammary adenocarcinomas developed in 16/40 in group 1 and 30/117 in group 2; no mammary tumors appeared in either control groups. The tumors were infiltrating adenocarcinomas often affecting more than one mammary gland; metastases were occasionally observed. Animals killed after 1 year of MPA treatment presented deciduomas. MPA also decreased the incidence of FB-induced sarcomas, confirming previous results.

Antiprogestins in breast cancer treatment: are we ready?

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. It is accepted that breast cancer is not a single disease, but instead constitutes a spectrum of tumor subtypes with distinct cellular origins, somatic changes, and etiologies. Molecular gene expression studies have divided breast cancer into several categories, i.e. basal-like, ErbB2 enriched, normal breast-like (adipose tissue gene signature), luminal subtype A, luminal subtype B, and claudin-low. Chances are that as our knowledge increases, each of these types will also be subclassified. More than 66% of breast carcinomas express estrogen receptor alpha (ERα) and respond to antiestrogen therapies. Most of these ER+ tumors also express progesterone receptors (PRs), the expression of which has been considered as a reliable marker of a functional ER. In this paper we will review the evidence suggesting that PRs are valid targets for breast cancer therapy. Experimental data suggest that both PR isoforms (A and B) have different roles in breast cancer cell growth, and antiprogestins have already been clinically used in patients who have failed to other therapies. We hypothesize that antiprogestin therapy may be suitable for patients with high levels of PR-A. This paper will go over the experimental evidence of our laboratory and others supporting the use of antiprogestins in selected breast cancer patients.

Plasma Cell Granuloma of the Bladder: A Case Report

We report a case of plasma cell granuloma of the bladder. Few cases of extrapulmonary localization have been described and none has been reported in the bladder. Immunocytochemical techniques identifying kappa and lambda immunoglobulin light chains confirmed the polyclonal nonneoplastic nature of the lesion.

Demonstration of Cytokeratins by Immunoperoxidase Staining in Prostatic Tissue

The presence and distribution of cytokeratins (CK) have been investigated using an epidermal keratin antiserum in various dilutions and the PaP (peroxidase-antiperoxidase) and avidin-biotin-peroxidase (ABC) immunohistochemical methods. A total of 44 samples of prostatic tissue were divided into alcohol-fixed (22 cases) and formaldehyde-fixed (22 cases). Each group included 12 non-malignant lesions (hyperplasias and prostatitis) and 10 adenocarcinomas. The best results were achieved with the ABC method in alcohol-fixed tissues, while formaldehyde-fixed tissues gave poor staining despite the use of different enzymes to unmask antigenic determinants. With similar dilutions of the specific antiserum the PaP method gave less intense staining. Cytokeratins were detected in basal and columnar cells, in areas of transitional and squamous metaplasia and in normal transitional epithelium. Columnar cells showed strong staining in the supranuclear portion. Adenocarcinomas gave positive staining for cytokeratins varying from weak to strong. The intensity of staining showed no correlation with the degree of differentiation of the tumor. Different degrees of intensity were frequently observed within the same tumor. High dilutions of the specific antiserum (greater than 1/400) failed to stain carcinomas or stained them poorly, whereas they still stained normal or hyperplastic tissues. Gland-forming tumors showed a highly polarized labelling with the strongest staining in the luminal portion of the cell. The conclusion is that all epithelial prostatic tissues, benign and malignant, express cytokeratins.

Progesterone receptors in estrogen-induced fibromatosis of guinea pigs

The presence of estrogen and progesterone receptors was investigated in estrogen-induced guinea pig fibromatosis. These lesions were composed of fibroblast-like cells embedded in abundant collagen which stained positively for desmin and vimentin suggesting muscler and fibroblast differentiation. Cytosolic progesterone receptors ranging from 13 to 2045 fmol/mg protein were present in 10/13 samples while nuclear progesterone receptors were detected in 7/10 samples with values ranging from 8 to 4639 fmol/mg DNA. The Kd of the cytosolic progesterone receptor measured by a Scatchard analysis yielded a value of 3.35 X 10(-9) M with a sedimentation coefficient of 9S as determined by a sucrose gradient. Estrogen nuclear binders were found in 9/10 samples ranging from 6 to 282 fmoles/mg DNA and cytosolic estrogen binders in 10/13 with values of 9 to 349 fmoles/mg protein. The Kd of the cytosolic estrogen binder was 22 X 10(-9) M. This binder was not detected by a commercially available monoclonal antibody. Estrogen cytosolic binders and progesterone cytosolic receptors were also detected in some samples of non tumoral fibrotic tissue. It is concluded that this experimental model is appropriate for the investigation of the effects of estrogen and progesterone on proliferative fibroblastic lesions.

Pathogenesis of Ductal and Lobular Progestin-Induced Mammary Carcinomas in BALB/c Mice

Several years ago, we demonstrated that medroxyprogesterone acetate (MPA)- induced mammary adenocarcinomas in female BALB/c mice with an incidence close to 80% and a mean latency of around 13 months (1). These tumors were mostly ductal, progestin-dependent (PD) adenocarcinomas with high levels of estrogen and progesterone receptors (ER and PR) (2). We later found that progesterone (P) also induced mammary carcinomas, but this time the tumors were mostly lobular, progestin-independent (PI) adenocarcinomas with lower levels of ER and PR (3). There was a constant correlation between progestin dependence and morphology, that is, lobular carcinomas were always PI and ductal carcinomas PD (3). To extend this study further, we designed a model of co-carcinogenesis using medroxyprogesterone (MPA) with N-methyl N-nitrosourea (MNU) in BALB/c mice. We obtained a high incidence of mammary adenocarcinomas similar to the hormone-induced lobular tumors, and showed that MPA can act as a potent promoter.