ROLE OF RET RECEPTOR TYROSINE KINASE AT THE POST-LACTATIONAL TRANSITION, A WINDOW OF NORMAL MAMMARY GLAND DEVELOPMENT WITH HIGH INFLAMMATION AND CANCER POTENTIAL

NANCY E. HYNES; MARTIN GARCIA SOLÁ; ALBANA GATTELLI; LEWIS A. CHODOSH; SABRINA VALLONE; EDITH C. KORDON; ROBERT D. CARDIFF

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Investigación Clínica (SAIC)

AbstractUnder the influence of hormones, the mammary gland undergoes repeated cycles of proliferation, differentiation at lactation, and regression to involution, a process through the gland reverts back to virgin females. Those changes permanently alter the morphology/molecular characteristics of the breast and lead to important, yet poorly understood changes in cancer risk. Her2, a member of the receptor tyrosine kinases (RTK) family is well known to promote aggressive breast cancers. We have reported that Ret, another RTK member, is overexpressed in about 40% of human tumors. It is well known that RTKs, e.g. the Her2, also have roles in normal breast, but nothing is known about the function of Ret. We found that Ret is highly expressed in the mouse glands during mid-lactation. Blocking Ret activity in lactation by in vivo administration of Ret inhibitor reduces pup size, suggesting its potential role in this period. We generated a mouse strain (Ret/MTB) with the MMTV mammary gland specific promoter controlling Ret expression in an inducible system, allowing induction of Ret by feeding mice with doxycycline. We found that abnormal Ret overexpression outside of the lactation, leads to the development of tumors that recapitulates human luminal carcinoma, with an inflammatory component and an active Stat signaling (phospho-Stat1/3). Since Ret expression can be turned-on in an inducible manner, we used this model to express Ret at different developmental stages. Indeed, Ret appears to have a role in the post-lactation transition to involution. When Ret is induced early in lactation we observe enhanced kinetics of involution. The involution period is well known to drive cancer progression. By RNA-seq we found that Stat signature is increased in Ret-overexpressing glands, which was confirmed by several techniques. Thus, our results suggest that if Ret expression is deregulated during the post-lactational transition this might contribute to breast cancer development.