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Abstract

The Sprague-Dawley rat is highly regarded for studies designed to investigate the effects of endocrine modulation on mammary carcinogenesis. In this study, we further evaluate the validity of the Sprague-Dawley rat model for the study of human breast cancer by evaluating the effects of normal 4-day estrous cycling on mammary epithelial cell proliferation, differentiation, and apoptotic death. Trends in mammary gland development with stage of 4-day estrous cycle were evident. Mammary glands isolated from follicular and early luteal stages had predominantly ductal histoarchitecture, whereas glands isolated from mid-late luteal were predominantly lobuloalveolar. Quantitation of BrdU incorporation revealed that epithelial cell proliferation was eight-fold higher in metestrus and diestrus-1 than in proestrus. Expression of beta-casein and whey acidic protein (WAP)4 mRNA was also highly dependent on stage of estrous, with detection restricted to midcycle. Apoptotic cell death of mammary epithelium was found to be suppressed during the peak in cell proliferation. TRPM-2/ clusterin mRNA was elevated when apoptosis was low and milk protein mRNA levels were high, consistent with putative roles for TRPM-2/clusterin in inhibiting cell death in regressing tissues and inducing mammary epithelial cell differentiation. Cell proliferation, differentiation, and death occurred only in a subset of epithelial cells per estrous cycle, and these cells appeared randomly distributed throughout multiple ductules and alveoli. These observations suggest that cellular response(s) to ovarian hormone-dependent signals is asynchronous. Cumulatively, these observations demonstrate that rat mammary epithelial cell proliferation, differentiation, and death are under the control of cycling ovarian hormones, similarly to the human mammary epithelium during the menstrual cycle.

Next-generation transcriptome sequencing of the premenopausal breast epithelium using specimens from a normal human breast tissue bank

“…Much of what is known about the specific changes in the normal mammary gland as a function of these hormones comes from the study of other mammals [11,12]. A large proportion of our knowledge of menstrual cycle effects in the human breast comes from histologic observations [13], and studies of markers of proliferation and apoptosis.…”

In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland

“…These studies have concerned the effects of the estrous cycle on proliferation in rats, and conflicting results have been observed (Schedin et al 2000, Hvid et al 2011. This study also examined the influence of the estrous cycle on a number of important markers involved in mammary gland morphogenesis in young virgin female rats (5 and 7 weeks respectively).…”

“…Subtle changes in the development of the mammary gland, such as proliferation and differentiation, have been described during the 4-5 days of transition during the rat estrous cycle (Schedin et al 2000, Hvid et al 2012). We reanalyzed the major changes in gene expression previously reported by quantitative RT-PCR data for individual RNA expression (as described in Tables 1 and 2), taking into account the stage of the estrous cycle (i.e.…”

Altered gene expression profile in chemically induced rat mammary adenocarcinomas and its modulation by an aromatase inhibitor

“…These tumors exhibit similarities with the human ER+ breast tumors including: (1) similar histopathology; (2) site of origin; and (3) response to various hormonal manipulations, e.g., ovariectomy, tamoxifen, pregnancy, and so forth (Gould, 1995;Russo, 1996, 2000;Schedin et al, 2000;Thompson et al, 2000). Consequently, this animal model has been used extensively for evaluating preventative and therapeutic agents of breast cancer Dukes, 1997).…”