Prolactin pathways and metastatic progression of ER-positive breast cancer

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DESCRIPTION (provided by applicant): Estrogen receptor-� positive (ER�+) breast cancer (BC) represents 70-80% of newly diagnosed cases. While potentially responsive to anti-estrogens, progression of ER�+ BC to anti-estrogen refractory disease in the metastatic setting is a common occurrence. Endocrine resistance mechanisms may differ between subtypes of ER�+ BC and involve both ER�-independent and ER�-dependent forms that remain poorly understood. Prolactin (PRL) interacts with estrogens to stimulate growth of certain subtypes of ER�+ BC. At the same time, the PRL-Jak-Stat5 pathway promotes differentiation and inhibits invasive features of BC, and loss of Stat5a signaling in a subgroup of ER�+ BC is associated with anti-estrogen therapy failure. The involvement of PRL pathways in growth and progression of anti-estrogen refractory BC subtypes remains to be determined. There is a lack of preclinical human ER�+ BC models that recapitulate progression from localized mammary gland growth to distant metastasis. Xenografts of patient-derived ER�+ BC exhibit poor take rate in mice. We have discovered that murine PRL is a poor agonist and a potent antagonist for human PRL receptor (PRLr). Bovine PRL is also a poor agonist with antagonist activity for human PRLr. Laboratory human BC lines therefore have been selected for PRL-independent growth and may only represent subtype(s) of ER�+ BC. To address this problem, we generated hPRL knock-in mice in the immunodeficient Nod-Scid-IL2R? strain that express physiological levels of circulating hPRL. Remarkably, PRL-humanized mice display greatly increased take rate of patient-derived xenografts of ER�+ BC. We established a panel of serially transplantable ER�+ Luminal B lines, several of which spontaneously metastasize to lungs and liver. The distant metastases become anti-estrogen refractory despite continued expression of ER�, but show PRL-dependence. Our long-range goal is to determine mechanisms of anti-estrogen refractoriness of BC to improve clinical management. Aim 1 is focused on Luminobasal subtype of BC (ER�+/CK5+) and explores a distinct ER�-independent mechanism of anti-estrogen refractory BC recently recognized in pre-existing ER�+ laboratory cell lines. We hypothesize that in Luminobasal BC, loss of PRL-Stat5 signaling promotes loss of ER� and subsequent anti-estrogen resistance due to defective Stat5a-driven differentiation. Aims 2 and 3 are focused on the Luminal B BC subtype (ER�+/CK5-/Ki67high) and will use PRL-dependent patient-derived xenograft lines. Aim 2 will test the hypothesis that in Luminal B BC, unlike in Luminobasal BC, PRL facilitates growth and survival of metastases and that PRLr-pathway targeting cooperates with anti-estrogens to eliminate distant metastases. Aim 3 will explore novel strategies for detecting and monitoring latent residual disease.