Mammary gland development—It’s not just about estrogen

Abstract

The mammary gland (MG) is one of a few organs that undergoes most of its growth after birth. Much of this development occurs concurrently with specific reproductive states, such that the ultimate goal of milk synthesis and secretion is coordinated with the nutritional requirements of the neonate. Central to the reproductive–MG axis is its endocrine regulation, and pivotal to this regulation is the ovarian secretion of estrogen (E). Indeed, it is widely accepted that estrogens are essential for growth of the MG to occur, both for ductal elongation during puberty and for alveolar development during gestation. As the factors regulating MG development continually come to light from the fields of developmental biology, lactation physiology, and breast cancer research, a growing body of evidence serves as a reminder that the MG are not as exclusively dependent on estrogens as might have been thought. The objective of this review is to summarize the state of information regarding our understanding of how estrogen (E) has been implicated as the key regulator of MG development, and to highlight some of the alternative E-independent mechanisms that have been discovered. In particular, we review our findings that dietary trans-10,cis-12 conjugated linoleic acid promotes ductal elongation and that the combination of progesterone (P) and prolactin (PRL) can stimulate branching morphogenesis in the absence of E. Ultimately, these examples stand as a healthy challenge to the question of just how important estrogens are for MG development. Answers to this question, in turn, increase our understanding of MG development across all mammals and the ways in which it can affect milk production.

Conjugated Linoleic Acid Administration Induces Amnesia in Male Sprague Dawley Rats and Exacerbates Recovery from Functional Deficits Induced by a Controlled Cortical Impact Injury

“…The maintenance of longer-term memories has been associated with the presence of sex steroids [ 59 ] and neurogenesis in the adult brain [ 60 ]. CLA’s have significant impacts on cell proliferation and differentiation, as evidenced by their effects on mammary ductal elongation and terminal end-bud formation (mediated via IGF-1; [ 61 ]), and its suppression of chemical carcinogen-induced mammary tumor burden in rats [ 62 , 63 ]. In this respect, increasing neurogenesis after the formation of a memory has been shown to be sufficient to induce forgetting in adult mice [ 60 ].…”

“…However, in contrast, during infancy, when hippocampal neurogenesis levels are high and freshly generated memories tend to be rapidly forgotten (infantile amnesia), decreasing neurogenesis after memory formation has been shown to mitigate forgetting. In addition to neurogenesis-related impacts on memory formation, the dietary 10,12 CLA isomer can elicit inflammatory responses that includes the recruitment of immune cells such as macrophages and mast cells, and an inflammatory state at both the systemic and tissue levels that manifests as decreased serum adiponectin and elevated IL-6 and tumor necrosis factor-α mRNA in adipose tissue (reviewed in [ 61 ]). Inflammation is associated with memory loss in Alzheimer’s disease.…”

“…Interestingly, high doses of CLA (50–200 uM) but not low doses (15–25 uM), increase P 4 production from bovine oocytes during in vitro maturation of parthenogenetic embryos [ 104 ]. That CLA may regulate steroidogenesis is suggested by studies demonstrating that trans-10,cis-12 conjugated linoleic acid promotes ductal elongation, since P 4 and prolactin, independent of E 2 , are well-known to induce branching morphogenesis [ 61 , 105 ].…”

The oxytocin receptor signalling system and breast cancer: a critical review

“…Breast cancer risk is affected by a variety of factors, including reproductive history and lifetime hormonal exposure, which also influences the course of the disease [29]. Oestrogen, progesterone and prolactin are well-studied hormonal regulators of mammary gland development [27,29,30]; less is known however about the regulatory roles of OT/OTR during breast development and tumorigenesis.…”

Comparison of methods to assess onset of breast development in the LEGACY Girls Study: methodological considerations for studies of breast cancer

“…Given the need to have scalable methods that accurately reflect pubertal development stage, the purpose of the present study was to compare the SMS and PDS with clinical TS to assess the specificity and sensitivity of reported measures of breast onset. Given that estrogens lead to increased epithelial proliferation in terminal end buds of the mammary gland, resulting in the onset of breast development [ 13 ], a secondary aim of this study was to evaluate whether the assessment of hormonal measures in premenarcheal girls increases the validity of guardian-reported methods of breast onset. Estrone 1-glucuronide (E1G), an estrogen metabolite in urine, is an indicator of total circulating estrogens, which rise before puberty [ 14 ].…”