Hoxd10 Is Required Systemically for Secretory Activation in Lactation and Interacts Genetically with Hoxd9

AbstractTargeted disruption of the murineHoxd10 gene( ΔHoxd10) leads to a high frequency of localized (gland-to-gland or regionally within a gland) lactation impairment in homozygous mutant mice as a single gene mutation. The effect ofHoxd10 disruption was enhanced by simultaneous disruption ofHoxd9 ( ΔHoxd9/d10), a mutation shown previously to have no effect on mammary function as a single gene alteration. Mammary glands of homozygousΔHoxd10 andΔHoxd9/d10 females were indistinguishable from those of wild type littermate and age-matched control mice in late pregnancy. However, in lactation, 47% of homozygousΔHoxd10 females, and 100% of homozygousΔHoxd9/d10 females, showed localized or complete failure of two or more glands to undergo lactation-associated morphological changes and to secrete milk. Affected regions ofΔHoxd10 andΔHoxd9/d10 mutants showed reduced prolactin receptor expression, reduced signal transducer and activator transcription protein 5 (STAT5) phosphorylation, reduced expression of downstream milk proteins, mislocalized glucose transporter 1 (GLUT1), increased STAT3 expression and phosphorylation, recruitment of leukocytes, altered cell cycle status, and increased apoptosis relative to unaffected regions and wild type control glands. Despite these local effects on alveolar function, transplantation results and hormone analysis indicate thatHoxd10 primarily has systemic functions that confer attenuated STAT5 phosphorylation on both wild type andΔHoxd1...

Source: Journal of Mammary Gland Biology and Neoplasia - July 22, 2020 Category: Cancer & Oncology Source Type: research