Publication Date

2013-04-24

Availability

Embargoed

Embargo Period

2015-04-24

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biochemistry and Molecular Biology (Medicine)

Date of Defense

2013-04-01

First Committee Member

Karoline J. Briegel

Second Committee Member

Ralf Landgraf

Third Committee Member

Feng Gong

Fourth Committee Member

Dorraya El-Ashry

Fifth Committee Member

David J. Robbins

Abstract

Breast cancer (BC) is the second leading cause of cancer-related death in women. Aggressive basal-subtype BCs contribute disproportionally to the number of cancer deaths and have no molecular targeted therapies currently available. Limb-Bud and Heart (LBH) is a novel transcription co-factor in the WNT pathway with hither-to unknown physiological function and is aberrantly overexpressed in poorly differentiated basal-subtype BCs. Here we show that in normal mammary epithelium of postnatal mice, LBH is predominantly expressed in the mammary stem cell (MaSC)-enriched basal cell subpopulation. Upon conditional inactivation of LBH function, mice exhibited a pronounced delay in pubertal mammary gland outgrowth, reduced terminal end bud cell proliferation, as well as increased luminal differentiation at the expense of basal myoepithelial differentiation. These defects could be traced to a severe reduction in the frequency and self-renewal/differentiation potential of MaSCs. We further demonstrate that LBH is required for BC stem cell (BCSC) formation and maintenance. Mechanistically, LBH induces expression of the key epithelial stem cell transcription factor ∆Np63 to promote a basal stem cell phenotype and repress expression of “good-prognosis” luminal lineage-specific genes, foremost Estrogen Receptor alpha (ERα). Collectively, this thesis work identified the first essential role of LBH in promoting MaSC function and basal lineage specification in both normal and cancerous settings. Our findings provide important novel insight into the etiology of ‘triple-negative’ BC, and suggest that inhibition of LBH could be used as a method of ‘differentiation therapy’ to re-sensitize tumor cells to known endocrine therapies against ERα.

Keywords

LBH; Mammary Stem Cell; Breast Cancer; Mammary Gland; WNT

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