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The influence of Her2 status on mammary stem/progenitor cells

Final Report Summary - HER2 MAMMARYSTEMCELL (The influence of Her2 status on mammary stem/progenitor cells)

INTRODUCTION
Breast cancer is a heterogeneous disease with distinct clinical outcomes. ERBB2-associated breast tumours have been proposed to arise from ERBB2 amplification/over-expression in luminal progenitor cells. However, this remains to be demonstrated, and the role of Erbb2 in the normal mammary epithelium is still unclear. Hence, it is important not only to better characterise the origin and development of this tumour type in mouse models, but also to explore the role of Erbb2 in the normal mammary gland epithelium as well as in the pre-neoplastic mouse mammary gland of mouse tumour models. Results from animal models will eventually be translated to human.

SOCIO ECONOMIC IMPACT
Breast cancer with ERBB2 over-expression is one of the most aggressive forms of this disease and represents ~25% of breast carcinomas. Breast cancer patients with ERBB2 over-expression can benefit from molecular therapies, but there are some who develop treatment resistance.

PROJECT AIMS
a) To investigate the role of Erbb2 and Erbb gene family members in normal mouse mammary glands.

b) To characterise the association of Erbb2 with cell of origin and tumour development of Erbb2-associated breast cancers, via identification of potential cancer stem cells in mouse Erbb2 tumours as well as oncogenic Erbb2 expression targeted to different mammary mouse cell lineages.

MAIN RESULTS
* Description of a complex paracrine Erbb cell signalling network between luminal and basal cell compartments, which is disrupted in MMTV-Neu pre-neoplastic tissues and mammary tumours. Ligands mostly produced by the basal compartment (stem and myoepithelial cells) such as Nrg1 or Nrg2, are recognized by receptors with higher expression in luminal fractions (Er-negative and positive), such as Erbb3 and Erbb4. Conversely, ligands produced by luminal compartment, such as Areg or Epgn, are recognized by receptors mostly expressed in basal fractions, such as Egfr (Figure 1A). However, all MMTV-Neu cell fractions over-expressed Erbb2/Neu and Erbb3, together with Egf when compared to their normal counterparts (Figure 1B). This was also seen in MMTV-Neu tumour cells, together with Areg down-regulation and Nrg2 up-regulation (Figure 1C).

* Driving effect of the over-expression of neuT in transformation of mouse mammary gland. NeuT was able not only to alter the size of transduced luminal cell colonies in 3D matrigel-cultures, but also to generate tumours when transduced mammary cells were transplanted into cleared mammary fat pads.

* MMTV-Neu tumour cells seem to all have tumour initiating capacities, and to recapitulate the tumour phenotype of the original tumour, when injected into mouse hosts.

* Establishment of two new Erbb2 mouse mammary tumour models: Blg-Cre neuKI and K14-Cre neuKI. Expression of the oncogenic form of Neu restricted to the luminal cell lineage (Blg-Cre neuKI) already caused mammary tumours, whose formation was accelerated under pregnancy cycles.

CONCLUSIONS
1) Changes in the expression of Erbb gene family members occur in the pre-neoplastic mammary tissue and are maintained in tumour cells (Figure 1). This abnormal autocrine cell signalling may influence the origin and development of mammary carcinomas in one mouse tumour model (MMTV-Neu).

2) Over-expression of an oncogenic form of Erbb2 in mouse primary mammary gland cells is able to produce mammary carcinomas, indicating the leading role of Erbb2 in the carcinogenesis process.

3) New mouse mammary tumour models have been established and, even more, one of them has showed mammary tumour formation with a relatively short latency.

More studies are still needed to better understand the Erbb2 role in normal and pre-neoplastic mammary glands, but it is likely that Erbb2 overexpression drives carcinogenesis by altering its relation with other Erbb family members, disrupting normal cell signalling network. These other Erbb family members would be interesting as prospective avenues for therapy of these aggressive cancers.