Abstract
Around 70% of breast cancers express the estrogen receptor alpha (ERα). This receptor is of central importance for breast cancer development and estrogen-dependent tumor growth. However, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast carcinogenesis are complex and not fully understood. In previous work, we have demonstrated that the tumor suppressor RASSF1A suppresses estrogen-dependent growth of breast cancer cells through a complex network that keeps ERα expression and function under control. We observed that RASSF1A mediates the suppression of ERα expression through modulation of the Hippo effector Yes-associated protein 1 (YAP1) activity. Here we report that RASSF1A-mediated alteration of YAP1 depends on the Hippo-kinases LATS1 and LATS2. Based on these results, we conclude that inactivation of RASSF1A causes changes in the function of the Hippo signaling pathway and altered activation of YAP1, and as a consequence, increased expression and function of ERα. Thus, the inactivation of RASSF1A might constitute a fundamental event that supports the initiation of ERα-dependent breast cancer. Furthermore, our results support the notion that the Hippo pathway is important for the suppression of luminal breast cancers, and that the tumor-suppressor function of RASSF1A depends on LATS1 and LATS2.
Highlights
The vast majority of breast cancers express the estrogen receptor alpha (ERα)
As Ras-associated domain family 1 isoform A (RASSF1A) is a key regulator of the Hippo pathway, and Hippo signaling plays an important role in the control of ERα function and the suppression of luminal breast cancer, we hypothesized that RASSF1A may exert some of its suppressive effects on
We show that RASSF1A acts as a tumor suppressor in ERα-expressing breast cancer cells by counteracting ERα expression and function, inhibiting cell cycle progression and inducing senescence
Summary
The vast majority of breast cancers express the estrogen receptor alpha (ERα). This receptor plays a fundamental role in normal breast physiology, abnormal expression and changes in the functional regulation of ERα foster the development and progression of breast cancer [1]. FOXM1 expression is activated by ERα in the presence of estrogens [2]. This is consistent with the observation that elevated expression of FOXM1 in breast cancer strongly correlates with ERα expression [2,3]. FOXM1 is an important regulator of the mitogenic functions of ERα in breast tumor cells, and increased expression of FOXM1 subsequently might contribute to ERα+ breast cancer initiation and progression as FOXM1 triggers cell cycle progression and circumvents induction of senescence [4]
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