Recombinant protein C affects mammary gland function

University Of Colorado Denver, Aurora CO

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Abstract

DESCRIPTION (provided by applicant): During pregnancy, the mammary gland undergoes morphological and biochemical changes to achieve final secretory differentiation. Failure to accomplish these changes is known to result in lactational failure - a problem for 3-15% of breastfeeding mothers. A potential model for the morphological and biochemical events associated with secretory activation is the whey acidic protein (WAP)/human protein C (hPC) transgenic mice. These mice exhibited small alveoli, impaired luminal expansion, reduced milk protein gene expression, and failed to lactate. The mammary epithelial cells had distinct, centrally located nuclei and contained large cytoplasmic lipid droplets associated with functionally inactive glands. A pilot microarray analysis of WAP/hPC mouse mammary gland RNA revealed significant (10 fold) upregulation of a transcriptional repressor protein called translocated ets leukemia (TEL). There is evidence to suggest that TEL transcription and activity is repressed during proliferation, and its overexpression may be linked to impaired tissue remodeling. I propose that homozygous expression of the WAP/hPC transgene aberrantly elevates TEL expression in alveolar epithelial cells, repressing their normal proliferation and differentiation and leading to a failure to lactate. The goal of this proposal is to define the role of TEL in generating the defects seen in WAP/hPC mice as well as its role in normal mammary gland development.