Cyclin D1 Kinase Activity Is Required for the Self-Renewal of Mammary Stem and Progenitor Cells that Are Targets of MMTV-ErbB2 Tumorigenesis

Abstract

Summary Transplantation studies have demonstrated the existence of mammary progenitor cells with the ability to self-renew and regenerate a functional mammary gland. Although these progenitors are the likely targets for oncogenic transformation, correlating progenitor populations with certain oncogenic stimuli has been difficult. Cyclin D1 is required for lobuloalveolar development during pregnancy and lactation as well as MMTV-ErbB2- but not MMTV-Wnt1-mediated tumorigenesis. Using a kinase deficient cyclin D1 mouse, we identified two functional mammary progenitor cell populations, one of which is the target of MMTV-ErbB2. Moreover, cyclin D1 activity is required for the self-renewal and differentiation of mammary progenitors as its abrogation leads to a failure to maintain the mammary epithelial regenerative potential and also results in defects in luminal lineage differentiation. Significance The cellular origins of breast cancer-initiating cells have remained obscure. In addition, the heterogeneity of breast cancers into basal and luminal types based on protein and gene expression patterns suggests that different subtypes of breast cancers might arise from different target populations of breast epithelial cells. Identification of distinct stem or progenitor cell populations with different hormonal sensitivities and requirements for cyclin D1 activity is appealing as it implies that the cellular origins of certain types of breast cancer may have a similar specificity. These specific requirements among tumor subtypes may offer therapeutic targets in human breast tumors.

Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer

“…MRK-003 similarly altered the differentiation of tumor cells, which normally express only luminallineage markers. Recent findings reveal that luminal progenitor cells may be the cells of origin of the Neuinduced tumors in the Neu (N202) transgenic strain (Jeselsohn et al, 2010). The effect of MRK-003 on mammary epithelial progenitor cell and tumor cell differentiation is consistent with an effect on Notch signaling; numerous studies have demonstrated that this pathway commits normal human and mouse mammary epithelial progenitor cells to the luminal fate and suppresses their differentiation toward the myoepithelial lineage (Buono et al, 2006;Bouras et al, 2008;Raouf et al, 2008;Yalcin-Ozuysal et al, 2010).…”

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

“…Consistently, PI-MECs can be found in both the basal and the luminal sorted compartments. 33,51,56 In addition, we cannot exclude the possibility that TAp63, alone or as a supporting factor, contributes to epithelial survival during involution. Indeed, TAp63 is localized in the luminal cells, 13,21 which are known to contain PI-MECs and some other mammary progenitors.…”

“…Indeed, one of the identified DNp63 target genes, integrin a6 (CD49f), is highly expressed in PI-MECs. 51,56 The study by Carroll et al 35 also highlights the crosstalk between p63-dependent cell adhesion and apoptosis. Specifically, on DNp63 knockdown MCF10A cells exhibit detachment and cell death via anoikis and apoptosis, whereas re-expression of integrin b4 partially rescues both cell adhesion and apoptosis.…”

“…Using the mouse model of HER2 breast cancer, mouse mammary tumor virus (MMTV)-driven ErbB2 (homolog of human HER2/ neu), 53 PI-MECs were shown to be cellular targets of HER2-mediated oncogenesis. [54][55][56] Indeed, ErbB2 tumorigenesis in mice increases with parity, and targeted removal of PI-MECs in vivo reduced tumor incidence in ErbB2 mice. [55][56][57] Likewise, clinical studies demonstrate that women during or right after pregnancy (when the number of PI-MECs is highest) have increased susceptibility for HER2 breast cancer.…”

“…[54][55][56] Indeed, ErbB2 tumorigenesis in mice increases with parity, and targeted removal of PI-MECs in vivo reduced tumor incidence in ErbB2 mice. [55][56][57] Likewise, clinical studies demonstrate that women during or right after pregnancy (when the number of PI-MECs is highest) have increased susceptibility for HER2 breast cancer. 58,59 Thus, we hypothesized that p63 hemizygosity would suppress ErbB2-mediated tumorigenesis as a consequence of a reduced PI-MEC pool.…”