Parity-induced mammary epithelial cells facilitate tumorigenesis in MMTV-neu transgenic mice

Abstract

Using a Cre-lox-based genetic labeling technique, we have recently discovered a parity-induced mammary epithelial subtype that is abundant in nonlactating and nonpregnant, parous females. These mammary epithelial cells serve as alveolar progenitors in subsequent pregnancies, and transplantation studies revealed that they possess features of multipotent progenitors such as self-renewal and the capability to contribute to ductal and alveolar morphogenesis. Here, we report that these cells are the cellular targets for transformation in MMTV-neu transgenic mice that exhibit accelerated mammary tumorigenesis in multiparous animals. The selective ablation of this epithelial subtype reduces the onset of tumorigenesis in multiparous MMTV-neu transgenics. There is, however, experimental evidence to suggest that parity-induced mammary epithelial cells may not be the only cellular targets in other MMTV-promoter-based transgenic strains. In particular, the heterogeneous MMTV-wnt1 lesions predominantly express the ductal differentiation marker Nkcc1 that is absent in MMTV-neu-derived tumors. Our observations support the idea that tumors originate from distinctly different epithelial subtypes in selected MMTV-promoter-driven cancer models and that diverse oncogenes might exert discrete effects on particular mammary epithelial subtypes.

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

“…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.…”

Stem Cells, Hormones, and Mammary Cancer

“…Transgenic mice expressing the wild type Her2/neu (ErbB2) oncogene under transcriptional regulation of the MMTV-LTR seem to be suitable for studying the involvement of PI-MEC in pregnancy-associated mammary tumorigenesis since this animal model exhibits a relatively long latency of tumorigenesis (T50 of 205 days). Using this animal model, we demonstrated that: a) multiparous females consistently exhibited accelerated tumorigenesis compared to their nulliparous littermate controls in a mixed genetic background and b) PI-MEC were, indeed, primary targets of neoplastic transformation in this model [19]. The de novo generation and amplification of a large number of hormone-responsive and apoptosisresistant epithelial cells (i.e.…”

The Genomic Signature of Breast Cancer Prevention

“…Studies at the molecular level using different platforms for global genome analysis have confirmed the universality of this phenomenon in various strains of rats and mice [13][14][15][16][17][18][19][20][21]. Studies in experimental animal models have been useful for uncovering the sequential genomic changes occurring in the mammary gland in response to multiple hormonal stimuli of pregnancy that lead to the imprinting of a permanent genomic signature.…”

“…In these models, the initiation of cancer is prevented by the differentiation of the mammary gland induced by pregnancy [11,12]. The molecular changes involved in this phenomenon are just starting to be unraveled [13][14][15][16][17][18]. The protection conferred by pregnancy is age-specific since a delay in childbearing after age 24 progressively increases the risk of cancer development.…”