Mammary Development and the Role of Leptin

Ong, Eddie (2002) Mammary Development and the Role of Leptin. PhD thesis, University of Glasgow.

Abstract

The control of mammary gland morphogenesis is very complex, involving autocrine, paracrine and endocrine factors. The obligate requirement for adipose tissue during early development has been well established but the reason(s) has yet to be resolved. In the first part of our study, we investigated how this intimate association of the gland with adipose tissue affects development. Mammary cell proliferation and apoptosis were quantified in mice from weaning through until maturity. Cell proliferation was relatively constant in virgin mice, irrespective of age, whilst apoptosis was much lower in aged mice, and varied in a way which is deserving of further studies, as it could have significant implications for pathological mammary development and breast cancer. During pregnancy, proliferation increased from a barely-detectable level at the start of gestation to a maximum in mid-pregnancy. High levels were maintained through until day 1 of lactation and measurable proliferation continued throughout lactation. Apoptosis was absent until the very end of pregnancy, was high immediately post-partum but then decreased before reaching its maximum during post-lactational involution. Cell proliferation did not differ significantly between a first and second lactation, whereas the postpartum surge of apoptosis was only observed in a first lactation starting early in life. It was also demonstrated that lactational history affects the way in which the gland proliferates and undergoes apoptosis during oestrous cycles late in life. Proliferation was reduced by a previous lactation, but apoptosis was not significantly affected. This also has implications for breast cancer incidence. Next, we examined the hypothesis if leptin, an endocrine product of adipose tissue, alters mammary development, using a combination of in vitro mammary culture techniques and in vivo murine models of leptin deficiency. Caprine and murine mammosphere cultures were used to test the effects of leptin of murine and ovine origin on mammary cell differentiation and the proliferation of ovine mammary cell culture. There was no reproducible evidence of a direct effect of leptin on mammary differentiation, either using ovine or murine leptin in both caprine and murine mammospheres. Neither did leptin affect mammary cell proliferation in cell culture. Nonetheless, wholemount analysis showed that mammary development in leptin deficient ob/ob mice is impaired. These mice had reduced ductal growth and increase size of fat pad. To determine whether leptin was directly responsible or it is just the failure of these mice to reach puberty, oestrogen and progesterone were administered as subcutaneous implants. Treatment with mammogens stimulated mammary cell proliferation in both wildtype and ob/ob mice. Based on the in vitro and in vivo studies, we can conclude that leptin per se is not essential for mammary development and the defect observed was an indirect consequence of the fact that ob/ob mice are sterile.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Chris Knight
• Keywords: Developmental biology
• Date of Award: 2002
• Depositing User: Enlighten Team
• Unique ID: glathesis:2002-76213
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Dec 2019 09:15
• Last Modified: 19 Dec 2019 09:15
• URI: https://theses.gla.ac.uk/id/eprint/76213